Designer Drug Research Unit – Publications

@article{pmid39636099,

title = {Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-,-dimethyltryptamine Analogs in Mice},

author = {Grant C Glatfelter and Allison A Clark and Natalie G Cavalco and Antonio Landavazo and John S Partilla and Marilyn Naeem and James A Golen and Andrew R Chadeayne and David R Manke and Bruce E Blough and John D McCorvy and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/39636099/},

doi = {10.1021/acschemneuro.4c00513},

issn = {1948-7193},

year  = {2024},

date = {2024-12-01},

urldate = {2024-12-01},

journal = {ACS Chem Neurosci},

volume = {15},

number = {24},

pages = {4458--4477},

abstract = {5-methoxy-,-dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its -alkyl, -allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT) and 1A receptors (5-HT), and 3) to examine the influence of 5-HT on 5-HT-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.g., 5-HT receptor subtypes, alpha adrenergic receptors), including potent effects at 5-HT and 5-HT. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED range = 0.2-1.8 mg/kg) and maximal effects ( range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED range = 3.2-20.6 mg/kg). 5-HT antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT antagonist pretreatment enhanced HTRs. In general, ,-dialkyl and -isopropyl derivatives displayed HTR activity, while the -methyl, -ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT unmasked latent HTR activity for the -ethyl analog and markedly increased maximal responses for other HTR-active compounds (40-90 HTRs/30 min), supporting the notion that 5-HT agonist activity can dampen 5-HT-mediated HTRs. Suppression of 5-HT-mediated HTRs by 5-HT only occurred after high 5-MeO-DMT doses, suggesting involvement of other receptors in modulating psychedelic-like effects. Overall, our findings provide key information about the receptor target profiles for 5-MeO-DMT analogs, the structure-activity relationships for inducing psychedelic-like effects, and the critical role of 5-HT agonism in modulating acute psychoactive effects of 5-HT agonists.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39521025,

title = {Characterization of novel nitazene recreational drugs: Insights into their risk potential from in vitro µ-opioid receptor assays and in vivo behavioral studies in mice},

author = {Marthe M Vandeputte and Grant C Glatfelter and Donna Walther and Nathan K Layle and Danielle M St Germaine and István Ujváry and Donna M Iula and Michael H Baumann and Christophe P Stove},

url = {https://pubmed.ncbi.nlm.nih.gov/39521025/},

doi = {10.1016/j.phrs.2024.107503},

issn = {1096-1186},

year  = {2024},

date = {2024-12-01},

urldate = {2024-12-01},

journal = {Pharmacol Res},

volume = {210},

pages = {107503},

abstract = {2-Benzylbenzimidazole derivatives or 'nitazenes' are increasingly present on the recreational drug market. Here, we report the synthesis and pharmacological characterization of 15 structurally diverse nitazenes that might be predicted to emerge or grow in popularity. This work expands the existing knowledge about 2-benzylbenzimidazole structure-activity relationships (SARs), while also helping stakeholders (e.g., forensic toxicologists, clinicians, policymakers) in their risk assessment and preparedness for the potential next generation of nitazenes. In vitro µ-opioid receptor (MOR) affinity was determined via competition radioligand ([H]DAMGO) binding assays in rat brain tissue. MOR activation (potency and efficacy) was studied by means of a cell-based β-arrestin 2 recruitment assay. For seven nitazenes, including etonitazene, opioid-like pharmacodynamic effects (antinociception, locomotor activity, body temperature changes) were evaluated after subcutaneous administration in male C57BL/6 J mice. The results showed that all nitazenes bound to MOR with nanomolar affinities, and the functional potency of several of them was comparable to or exceeded that of fentanyl. In vivo, dose-dependent effects were observed for antinociception, locomotor activity, and body temperature changes in mice. SAR insights included the high opioid-like activity of methionitazene, iso-butonitazene, sec-butonitazene, and the etonitazene analogues 1-ethyl-pyrrolidinylmethyl N-desalkyl etonitazene and ethylene etonitazene. The most potent analogue of the panel across all functional assays was α'-methyl etonitazene. Taken together, through critical pharmacological evaluation, this work provides a framework for strengthened preparedness and risk assessments of current and future nitazenes that have the potential to cause harm to users.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38965085,

title = {Reinforcing effects of fentanyl analogs found in illicit drug markets},

author = {Alexander D Maitland and Shelby A McGriff and Grant C Glatfelter and Charles W Schindler and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/38965085/},

doi = {10.1007/s00213-024-06641-6},

issn = {1432-2072},

year  = {2024},

date = {2024-11-01},

urldate = {2024-11-01},

journal = {Psychopharmacology (Berl)},

volume = {241},

number = {11},

pages = {2375--2383},

abstract = {RATIONALE: The potent synthetic opioid fentanyl, and its analogs, continue to drive opioid-related overdoses. Although the pharmacology of fentanyl is well characterized, there is little information about the reinforcing effects of clandestine fentanyl analogs (FAs).nnOBJECTIVES: Here, we compared the effects of fentanyl and the FAs acetylfentanyl, butyrylfentanyl, and cyclopropylfentanyl on drug self-administration in male and female rats. These FAs feature chemical modifications at the carbonyl moiety of the fentanyl scaffold.nnMETHODS: Sprague-Dawley rats fitted with intravenous jugular catheters were placed in chambers containing two nose poke holes. Active nose poke responses resulted in drug delivery (0.2 mL) over 2 s on a fixed-ratio 1 schedule, followed by a 20 s timeout. Acquisition doses were 0.01 mg/kg/inj for fentanyl and cyclopropylfentanyl, and 0.03 mg/kg/inj for acetylfentanyl and butyrylfentanyl. After 10 days of acquisition, dose-effect testing was carried out, followed by 10 days of saline extinction.nnRESULTS: Self-administration of fentanyl and FAs was acquired by both male and female rats, with no sex differences in acquisition rate. Fentanyl and FAs showed partial inverted-U dose-effect functions; cyclopropylfentanyl and fentanyl had similar potency, while acetylfentanyl and butyrylfentanyl were less potent. Maximal response rates were similar across drugs, with fentanyl and cyclopropylfentanyl showing maximum responding at 0.001 mg/kg/inj, acetylfentanyl at 0.01 mg/kg/inj, and butyrylfentanyl at 0.003 mg/kg/inj. No sex differences were detected for drug potency, efficacy, or rates of extinction.nnCONCLUSIONS: Our work provides new evidence that FAs display significant abuse liability in male and female rats, which suggests the potential for compulsive use in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38481684,

title = {Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited},

author = {Grant C Glatfelter and Eline Pottie and John S Partilla and Christophe P Stove and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/38481684/},

doi = {10.1021/acsptsci.3c00192},

issn = {2575-9108},

year  = {2024},

date = {2024-03-01},

urldate = {2024-03-01},

journal = {ACS Pharmacol Transl Sci},

volume = {7},

number = {3},

pages = {641--653},

abstract = {Lisuride is a non-psychedelic serotonin (5-HT) 2A receptor (5-HT) agonist and analogue of the psychedelic lysergic acid diethylamide (LSD). Lisuride also acts as an agonist at the serotonin 1A receptor (5-HT), a property known to counter psychedelic effects. Here, we tested whether lisuride lacks psychedelic activity due to a dual mechanism: (1) partial agonism at 5-HT and (2) potent agonism at 5-HT. The  effects of lisuride, LSD, and related analogues on 5-HT signaling were characterized by using miniGα and β-arrestin 2 recruitment assays. The 5-HT- and 5-HT-mediated effects of lisuride and LSD were also compared in male C57BL/6J mice. The  results confirmed that LSD is an agonist at 5-HT, with high efficacy and potency for recruiting miniGα and β-arrestin 2. By contrast, lisuride displayed partial efficacy for both functional end points (6-52% of 5-HT or LSD ) and antagonized the effects of LSD. The mouse experiments demonstrated that LSD induces head twitch responses (HTRs)(ED = 0.039 mg/kg), while lisuride suppresses HTRs (ED = 0.006 mg/kg). Lisuride also produced potent hypothermia and hypolocomotion (ED = 0.008-0.023 mg/kg) that was blocked by the 5-HT antagonist WAY100635 (3 mg/kg). Blockade of 5-HT prior to lisuride restored basal HTRs, but it failed to increase HTRs above baseline levels. HTRs induced by LSD were blocked by lisuride (0.03 mg/kg) or the 5-HT agonist 8-OH-DPAT (1 mg/kg). Overall, our findings show that lisuride is an ultrapotent 5-HT agonist in C57BL/6J mice, limiting its use as a 5-HT ligand in mouse studies examining acute drug effects. Results also indicate that the 5-HT partial agonist-antagonist activity of lisuride explains its lack of psychedelic effects.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38189238,

title = {Psychedelic-like Activity of Norpsilocin Analogues},

author = {Alexander M Sherwood and Elise K Burkhartzmeyer and Samuel E Williamson and Michael H Baumann and Grant C Glatfelter},

url = {https://pubmed.ncbi.nlm.nih.gov/38189238/},

doi = {10.1021/acschemneuro.3c00610},

issn = {1948-7193},

year  = {2024},

date = {2024-01-01},

urldate = {2024-01-01},

journal = {ACS Chem Neurosci},

volume = {15},

number = {2},

pages = {315--327},

abstract = {Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT)  but differ in their 5-HT-mediated effects . In particular, psilocin produces centrally mediated psychedelic effects , whereas norpsilocin, differing only by the loss of an -methyl group, is devoid of psychedelic-like effects. These observations suggest that the secondary methylamine group in norpsilocin impacts its central nervous system (CNS) bioavailability but not its receptor pharmacodynamics. To test this hypothesis, eight norpsilocin derivatives were synthesized with varied secondary alkyl-, allyl-, and benzylamine groups, primarily aiming to increase their lipophilicity and brain permeability. Structure-activity relationships for the norpsilocin analogues were evaluated using the mouse head-twitch response (HTR) as a proxy for CNS-mediated psychedelic-like effects. HTR studies revealed that extending the -methyl group of norpsilocin by a single methyl group, to give the corresponding secondary -ethyl analogue (4-HO-NET), was sufficient to produce psilocin-like activity (median effective dose or ED = 1.4 mg/kg). Notably, -allyl, -propyl, -isopropyl, and -benzyl derivatives also induced psilocin-like HTR activity (ED = 1.1-3.2 mg/kg), with variable maximum effects (26-77 total HTR events). By contrast, adding bulkier -butyl or cyclohexyl groups in the same position did not elicit psilocin-like HTRs. Pharmacological assessments of the tryptamine series  demonstrated interactions with multiple serotonin receptor subtypes, including 5-HT, and other CNS signaling proteins (e.g., sigma receptors). Overall, our data highlight key structural requirements for CNS-mediated psychedelic-like effects of norpsilocin analogues.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37658878b,

title = {Alkoxy chain length governs the potency of 2-benzylbenzimidazole 'nitazene' opioids associated with human overdose},

author = {Grant C Glatfelter and Marthe M Vandeputte and Li Chen and Donna Walther and Meng-Hua M Tsai and Lei Shi and Christophe P Stove and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/37658878/},

doi = {10.1007/s00213-023-06451-2},

issn = {1432-2072},

year  = {2023},

date = {2023-12-01},

urldate = {2023-12-01},

journal = {Psychopharmacology (Berl)},

volume = {240},

number = {12},

pages = {2573--2584},

abstract = {RATIONALE: Novel synthetic opioids (NSOs) are emerging in recreational drug markets worldwide. In particular, 2-benzylbenzimidazole 'nitazene' compounds are problematic NSOs associated with serious clinical consequences, including fatal respiratory depression. Evidence from in vitro studies shows that alkoxy chain length can influence the potency of nitazenes at the mu-opioid receptor (MOR). However, structure-activity relationships (SARs) of nitazenes for inducing opioid-like effects in animal models are not well understood compared to relevant opioids contributing to the ongoing opioid crisis (e.g., fentanyl).nnOBJECTIVES: Here, we examined the in vitro and in vivo effects of nitazene analogues with varying alkoxy chain lengths (i.e., metonitazene, etonitazene, isotonitazene, protonitazene, and butonitazene) as compared to reference opioids (i.e., morphine and fentanyl).nnMETHODS AND RESULTS: Nitazene analogues displayed nanomolar affinities for MOR in rat brain membranes and picomolar potencies to activate MOR in transfected cells. All compounds induced opioid-like effects on locomotor activity, hot plate latency, and body temperature in male mice, and alkoxy chain length markedly influenced potency. Etonitazene, with an ethoxy chain, was the most potent analogue in MOR functional assays (EC = 30 pM, E = 103%) and across all in vivo endpoints (ED = 3-12 μg/kg). In vivo SARs revealed that ethoxy, isopropoxy, and propoxy chains engendered higher potencies than fentanyl, whereas methoxy and butoxy analogues were less potent. MOR functional potencies, but not MOR affinities, were positively correlated with in vivo potencies to induce opioid effects.nnCONCLUSIONS: Overall, our data show that certain nitazene NSOs are more potent than fentanyl as MOR agonists in mice, highlighting concerns regarding the high potential for overdose in humans who are exposed to these compounds.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37276825b,

title = {Comparative neuropharmacology of structurally distinct non-fentanyl opioids that are appearing on recreational drug markets worldwide},

author = {Marthe M Vandeputte and Meng-Hua M Tsai and Li Chen and Grant C Glatfelter and Donna Walther and Christophe P Stove and Lei Shi and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/37276825/},

doi = {10.1016/j.drugalcdep.2023.109939},

issn = {1879-0046},

year  = {2023},

date = {2023-08-01},

urldate = {2023-08-01},

journal = {Drug Alcohol Depend},

volume = {249},

pages = {109939},

abstract = {BACKGROUND: The emergence of novel synthetic opioids (NSOs) is contributing to the opioid overdose crisis. While fentanyl analogs have historically dominated the NSO market, a shift towards non-fentanyl compounds is now occurring.nnMETHODS: Here, we examined the neuropharmacology of structurally distinct non-fentanyl NSOs, including U-47700, isotonitazene, brorphine, and N-desethyl isotonitazene, as compared to morphine and fentanyl. Compounds were tested in vitro using opioid receptor binding assays in rat brain tissue and by monitoring forskolin-stimulated cAMP accumulation in cells expressing the human mu-opioid receptor (MOR). Compounds were administered subcutaneously to male Sprague-Dawley rats, and hot plate antinociception, catalepsy score, and body temperature changes were measured.nnRESULTS: Receptor binding results revealed high MOR selectivity for all compounds, with MOR affinities comparable to those of morphine and fentanyl (i.e., nM). All drugs acted as full-efficacy MOR agonists in the cyclic AMP assay, but nitazene analogs had greater functional potencies (i.e., pM) compared to the other drugs (i.e., nM). When administered to rats, all compounds induced opioid-like antinociception, catalepsy, and body temperature changes, but nitazenes were the most potent. Similar to fentanyl, the nitazenes had faster onset and decline of in vivo effects when compared to morphine. In vivo potencies to induce antinociception and catalepsy (i.e., EDs) correlated with in vitro functional potencies (i.e., ECs) but not binding affinities (i.e., Ks) at MOR.nnCONCLUSIONS: Collectively, our findings indicate that non-fentanyl NSOs pose grave danger to those individuals who use opioids. Continued vigilance is needed to identify and characterize synthetic opioids as they emerge in clandestine drug markets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37082754,

title = {Receptor Binding Profiles for Tryptamine Psychedelics and Effects of 4-Propionoxy--dimethyltryptamine in Mice},

author = {Grant C Glatfelter and Marilyn Naeem and Duyen N K Pham and James A Golen and Andrew R Chadeayne and David R Manke and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/37082754/},

doi = {10.1021/acsptsci.2c00222},

issn = {2575-9108},

year  = {2023},

date = {2023-04-01},

urldate = {2023-04-01},

journal = {ACS Pharmacol Transl Sci},

volume = {6},

number = {4},

pages = {567--577},

abstract = {Analogues of 4-phosphoryloxy--dimethyltryptamine (psilocybin) are being sold on recreational drug markets and developed as potential medications for psychedelic-assisted therapies. Many of these tryptamine-based psilocybin analogues produce psychedelic-like effects in rodents and humans primarily by agonist activity at serotonin 2A receptors (5-HT). However, the comprehensive pharmacological target profiles for these compounds compared to psilocybin and its active metabolite 4-hydroxy--dimethyltryptamine (psilocin) are unknown. The present study determined the receptor binding profiles of various tryptamine-based psychedelics structurally related to psilocybin across a broad range of potential targets. Specifically, we examined tryptamine psychedelics with different 4-position (hydroxy, acetoxy, propionoxy) and ,-dialkyl (dimethyl, methyl-ethyl, diethyl, methyl-propyl, ethyl-propyl, diisopropyl, methyl-allyl, diallyl) substitutions. Further, the psilocybin analogue 4-propionoxy--dimethyltryptamine (4-PrO-DMT) was administered to mice in experiments measuring head twitch response (HTR), locomotor activity, and body temperature. Overall, the present pharmacological profile screening data show that the tryptamine psychedelics target multiple serotonin receptors, including serotonin 1A receptors (5-HT). 4-Acetoxy and 4-propionoxy analogues of 4-hydroxy compounds displayed somewhat weaker binding affinities but similar target profiles across 5-HT receptors and other identified targets. Additionally, differential binding screen profiles were observed with -dialkyl position variations across several non-5-HT receptor targets (i.e., alpha receptors, dopamine receptors, histamine receptors, and serotonin transporters), which could impact  pharmacological effects of the compounds. In mouse experiments, 4-PrO-DMT displayed dose-related psilocybin-like effects to produce 5-HT-mediated HTR (0.3-3 mg/kg s.c.) as well as 5-HT-mediated hypothermia and hypolocomotion (3-30 mg/kg s.c.). Lastly, our data support a growing body of evidence that the 5-HT-mediated HTR induced by tryptamine psychedelics is attenuated by 5-HT receptor agonist activity at high doses in mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36730201,

title = {Persistent binding at dopamine transporters determines sustained psychostimulant effects},

author = {Marco Niello and Spyridon Sideromenos and Ralph Gradisch and Ronan O Shea and Jakob Schwazer and Julian Maier and Nina Kastner and Walter Sandtner and Kathrin Jäntsch and Carl R Lupica and Alexander F Hoffman and Gert Lubec and Claus J Loland and Thomas Stockner and Daniela D Pollak and Michael H Baumann and Harald H Sitte},

url = {https://pubmed.ncbi.nlm.nih.gov/36730201/},

doi = {10.1073/pnas.2114204120},

issn = {1091-6490},

year  = {2023},

date = {2023-02-01},

urldate = {2023-02-01},

journal = {Proc Natl Acad Sci U S A},

volume = {120},

number = {6},

pages = {e2114204120},

abstract = {Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow ) of -enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36526866,

title = {Plasma pharmacokinetics and pharmacodynamic effects of the 2-benzylbenzimidazole synthetic opioid, isotonitazene, in male rats},

author = {Sara E Walton and Alex J Krotulski and Grant C Glatfelter and Donna Walther and Barry K Logan and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/36526866/},

doi = {10.1007/s00213-022-06292-5},

issn = {1432-2072},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {Psychopharmacology (Berl)},

volume = {240},

number = {1},

pages = {185--198},

abstract = {RATIONALE: Isotonitazene is an illicit synthetic opioid associated with many intoxications and fatalities. Recent studies show that isotonitazene is a potent µ-opioid receptor (MOR) agonist in vitro, but little information is available about its in vivo effects.nnOBJECTIVES: The aims of the present study were to investigate the pharmacokinetics of isotonitazene in rats, and relate pharmacokinetic parameters to pharmacodynamic effects.nnMETHODS: Isotonitazene and its metabolites were identified and quantified by liquid chromatography tandem quadrupole mass spectrometry (LC-QQQ-MS). Male Sprague-Dawley rats with jugular catheters and subcutaneous (s.c.) temperature transponders received isotonitazene (3, 10, 30 µg/kg, s.c.) or its vehicle. Blood samples were drawn at 15, 30, 60, 120, and 240 min post-injection, and plasma was assayed using LC-QQQ-MS. At each blood draw, body temperature, catalepsy scores, and hot plate latencies were recorded.nnRESULTS: Maximum plasma concentrations of isotonitazene rose in parallel with increasing dose (range 0.2-9.8 ng/mL) and half-life ranged from 23.4 to 63.3 min. The metabolites 4'-hydroxy nitazene and N-desethyl isotonitazene were detected, and plasma concentrations were below the limit of quantitation (0.5 ng/mL) but above the limit of detection (0.1 ng/mL). Isotonitazene produced antinociception (ED = 4.22 µg/kg), catalepsy-like symptoms (ED = 8.68 µg/kg), and hypothermia (only at 30 µg/kg) that were significantly correlated with concentrations of isotonitazene. Radioligand binding in rat brain tissue revealed that isotonitazene displays nM affinity for MOR (Ki = 15.8 nM), while the N-desethyl metabolite shows even greater affinity (Ki = 2.2 nM).nnCONCLUSIONS: In summary, isotonitazene is a potent MOR agonist whose pharmacodynamic effects are related to circulating concentrations of the parent drug. The high potency of isotonitazene portends substantial risk to users who are exposed to the drug.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36407948,

title = {Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice},

author = {Grant C Glatfelter and Eline Pottie and John S Partilla and Alexander M Sherwood and Kristi Kaylo and Duyen N K Pham and Marilyn Naeem and Vamshikrishna Reddy Sammeta and Stacie DeBoer and James A Golen and Elliott B Hulley and Christophe P Stove and Andrew R Chadeayne and David R Manke and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/36407948/},

doi = {10.1021/acsptsci.2c00177},

issn = {2575-9108},

year  = {2022},

date = {2022-11-01},

urldate = {2022-11-01},

journal = {ACS Pharmacol Transl Sci},

volume = {5},

number = {11},

pages = {1181--1196},

abstract = {4-Phosphoryloxy-,-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-,-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT). Several other 4-position ring-substituted tryptamines are present in psilocybin-containing mushrooms, including the secondary amine 4-phosphoryloxy--methyltryptamine (baeocystin) and the quaternary ammonium 4-phosphoryloxy-,,-trimethyltryptamine (aeruginascin), but these compounds are not well studied. Here, we investigated the structure-activity relationships for psilocybin, baeocystin, and aeruginascin, as compared to their 4-acetoxy and 4-hydroxy analogues, using  and  methods. Broad receptor screening using radioligand binding assays in transfected cells revealed that secondary and tertiary tryptamines with either 4-acetoxy or 4-hydroxy substitutions display nanomolar affinity for most human 5-HT receptor subtypes tested, including the 5-HT and the serotonin 1A receptor (5-HT). The same compounds displayed affinity for 5-HT and 5-HT in mouse brain tissue  and exhibited agonist efficacy in assays examining 5-HT-mediated calcium mobilization and β-arrestin 2 recruitment. In mouse experiments, only the tertiary amines psilocin, psilocybin, and 4-acetoxy-,-dimethyltryptamine (psilacetin) induced head twitch responses (ED 0.11-0.29 mg/kg) indicative of psychedelic-like activity. Head twitches were blocked by 5-HT antagonist pretreatment, supporting 5-HT involvement. Both secondary and tertiary amines decreased body temperature and locomotor activity at higher doses, the effects of which were blocked by 5-HT antagonist pretreatment. Across all assays, the pharmacological effects of 4-acetoxy and 4-hydroxy compounds were similar, and these compounds were more potent than their 4-phosphoryloxy counterparts. Importantly, psilacetin appears to be a prodrug for psilocin that displays substantial serotonin receptor activities of its own.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35449307,

title = {First identification, chemical analysis and pharmacological characterization of N-piperidinyl etonitazene (etonitazepipne), a recent addition to the 2-benzylbenzimidazole opioid subclass},

author = {Marthe M Vandeputte and Nick Verougstraete and Donna Walther and Grant C Glatfelter and Jeroen Malfliet and Michael H Baumann and Alain G Verstraete and Christophe P Stove},

url = {https://pubmed.ncbi.nlm.nih.gov/35449307/},

doi = {10.1007/s00204-022-03294-2},

issn = {1432-0738},

year  = {2022},

date = {2022-06-01},

urldate = {2022-06-01},

journal = {Arch Toxicol},

volume = {96},

number = {6},

pages = {1865--1880},

abstract = {N-Piperidinyl etonitazene ('etonitazepipne') represents a recent addition to the rapidly expanding class of 2-benzylbenzimidazole 'nitazene' opioids. Following its first identification in an online-sourced powder and in biological samples from a patient seeking help for detoxification, this report details its in-depth chemical analysis and pharmacological characterization. Analysis of the powder via different techniques (LC-HRMS, GC-MS, UHPLC-DAD, FT-IR) led to the unequivocal identification of N-piperidinyl etonitazene. Furthermore, we report the first activity-based detection and analytical identification of N-piperidinyl etonitazene in authentic samples. LC-HRMS analysis revealed concentrations of 1.21 ng/mL in serum and 0.51 ng/mL in urine, whereas molecular networking enabled the tentative identification of various (potentially active) urinary metabolites. In addition, we determined that the extent of opioid activity present in the patient's serum was equivalent to the in vitro opioid activity exerted by 2.5-10 ng/mL fentanyl or 10-25 ng/mL hydromorphone in serum. Radioligand binding assays in rat brain tissue revealed that the drug binds with high affinity (K = 14.3 nM) to the µ-opioid receptor (MOR). Using a MOR-β-arrestin2 activation assay, we found that N-piperidinyl etonitazene is highly potent (EC = 2.49 nM) and efficacious (E = 183% versus hydromorphone) in vitro. Pharmacodynamic evaluation in male Sprague Dawley rats showed that N-piperidinyl etonitazene induces opioid-like antinociceptive, cataleptic, and thermic effects, its potency in the hot plate assay (ED = 0.0205 mg/kg) being comparable to that of fentanyl (ED = 0.0209 mg/kg), and > 190 times higher than that of morphine (ED = 3.940 mg/kg). Taken together, our findings indicate that N-piperidinyl etonitazene is a potent opioid with the potential to cause harm in users.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34802041b,

title = {Structure-activity relationships for 5F-MDMB-PICA and its 5F-pentylindole analogs to induce cannabinoid-like effects in mice},

author = {Grant C Glatfelter and John S Partilla and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/34802041/},

doi = {10.1038/s41386-021-01227-8},

issn = {1740-634X},

year  = {2022},

date = {2022-03-01},

urldate = {2022-03-01},

journal = {Neuropsychopharmacology},

volume = {47},

number = {4},

pages = {924--932},

abstract = {Synthetic cannabinoid receptor agonists (SCRAs) are an evolving class of new psychoactive substances found on recreational drug markets worldwide. The indole-containing compound, 5F-MDMB-PICA, is a popular SCRA associated with serious medical consequences, including overdose and hospitalizations. In vitro studies reveal that 5F-MDMB-PICA is a potent agonist at cannabinoid type 1 receptors (CB), but little information exists regarding in vivo pharmacology of the drug. To this end, we examined the in vitro and in vivo cannabinoid-like effects produced by 5F-MDMB-PICA and related 5F-pentylindole analogs with differing composition of the head group moiety (i.e., 5F-NNEI, 5F-SDB-006, 5F-CUMYL-PICA, 5F-MMB-PICA). In mouse brain membranes, 5F-MDMB-PICA and its analogs inhibited binding to [H]rimonabant-labeled CB and displayed agonist actions in [S]GTPγS functional assays. 5F-MDMB-PICA exhibited the highest CB affinity (K = 1.24 nM) and functional potency (EC = 1.46 nM), but head group composition markedly influenced activity in both assays. For example, the 3,3-dimethylbutanoate (5F-MDMB-PICA) and cumyl (5F-CUMYL-PICA) head groups engendered high CB affinity and potency, whereas a benzyl (5F-SDB-006) head group did not. In C57BL/6J mice, all 5F-pentylindole SCRAs produced dose- and time-dependent hypothermia, catalepsy, and analgesia that were reversed by rimonabant, indicating CB involvement. In vitro K and EC values were positively correlated with in vivo ED potency estimates. Our findings demonstrate that 5F-MDMB-PICA is a potent SCRA, and subtle alterations to head group composition can have profound influence on pharmacological effects at CB. Importantly, measures of CB binding and efficacy in mouse brain tissue seem to accurately predict in vivo drug potency in this species.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34750565,

title = {(2-Aminopropyl)benzo[β]thiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice},

author = {Deborah Rudin and John D McCorvy and Grant C Glatfelter and Dino Luethi and Dániel Szöllősi and Tea Ljubišić and Pierce V Kavanagh and Geraldine Dowling and Marion Holy and Kathrin Jaentsch and Donna Walther and Simon D Brandt and Thomas Stockner and Michael H Baumann and Adam L Halberstadt and Harald H Sitte},

url = {https://pubmed.ncbi.nlm.nih.gov/34750565/},

doi = {10.1038/s41386-021-01221-0},

issn = {1740-634X},

year  = {2022},

date = {2022-03-01},

urldate = {2022-03-01},

journal = {Neuropsychopharmacology},

volume = {47},

number = {4},

pages = {914--923},

abstract = {Derivatives of (2-aminopropyl)indole (API) and (2-aminopropyl)benzofuran (APB) are new psychoactive substances which produce stimulant effects in vivo. (2-Aminopropyl)benzo[β]thiophene (APBT) is a novel sulfur-based analog of API and APB that has not been pharmacologically characterized. In the current study, we assessed the pharmacological effects of six APBT positional isomers in vitro, and three of these isomers (3-APBT, 5-APBT, and 6-APBT) were subjected to further investigations in vivo. Uptake inhibition and efflux assays in human transporter-transfected HEK293 cells and in rat brain synaptosomes revealed that APBTs inhibit monoamine reuptake and induce transporter-mediated substrate release. Despite being nonselective transporter releasers like MDMA, the APBT compounds failed to produce locomotor stimulation in C57BL/6J mice. Interestingly, 3-APBT, 5-APBT, and 6-APBT were full agonists at 5-HT receptor subtypes as determined by calcium mobilization assays and induced the head-twitch response in C57BL/6J mice, suggesting psychedelic-like activity. Compared to their APB counterparts, ABPT compounds demonstrated that replacing the oxygen atom with sulfur results in enhanced releasing potency at the serotonin transporter and more potent and efficacious activity at 5-HT receptors, which fundamentally changed the in vitro and in vivo profile of APBT isomers in the present studies. Overall, our data suggest that APBT isomers may exhibit psychedelic and/or entactogenic effects in humans, with minimal psychomotor stimulation. Whether this unique pharmacological profile of APBT isomers translates into potential therapeutic potential, for instance as candidates for drug-assisted psychotherapy, warrants further investigation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33689284,

title = {Eutylone and Its Structural Isomers Interact with Monoamine Transporters and Induce Locomotor Stimulation},

author = {Grant C Glatfelter and Donna Walther and Michael Evans-Brown and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/33689284/},

doi = {10.1021/acschemneuro.0c00797},

issn = {1948-7193},

year  = {2021},

date = {2021-04-01},

urldate = {2021-04-01},

journal = {ACS Chem Neurosci},

volume = {12},

number = {7},

pages = {1170--1177},

abstract = {Synthetic cathinones are a class of new psychoactive substances that induce psychostimulant effects and pose risk for hospitalizations, overdose, and death. At the present time, derivatives of the synthetic cathinone, methylone, are being confiscated in nonmedical (i.e., recreational) drug markets worldwide. In particular, eutylone is a newly emerging methylone analog that possesses ethyl groups at the α-carbon and amine positions. Little information is available about the pharmacological effects of eutylone, but based on its structure, we surmised that the compound interacts with monoamine transporters in the brain. To test this hypothesis, we compared the effects of eutylone and its structural isomers, dibutylone and pentylone, using  transporter assays in rat brain synaptosomes and  locomotor activity assessments in mice. All drugs displayed dose-related inhibition of [H]neurotransmitter uptake at dopamine transporters (DAT) and norepinephrine transporters (NET), but effects at DAT were 10-fold more potent (IC = 120 nM). Eutylone and pentylone inhibited uptake at serotonin transporters (SERT), while dibutylone did not. Additionally, eutylone and pentylone displayed weak partial releasing actions at SERT which achieved 50% of maximal response. All drugs stimulated dose-related locomotion in mice, and eutylone was most potent and efficacious in this regard (ED = 2 mg/kg, sc). Our results demonstrate that eutylone is a hybrid transporter compound with uptake inhibition properties at DAT and NET but substrate activity at SERT. The effects of eutylone are similar to those produced by pentylone, which suggests that eutylone will exhibit abuse liability and pose risks for psychostimulant side-effects in human users.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Schindler118,

title = {Amphetamine-like Neurochemical and Cardiovascular Effects of \textit{α}-Ethylphenethylamine Analogs Found in Dietary Supplements},

author = {Charles W Schindler and Eric B Thorndike and John S Partilla and Kenner C Rice and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/33082158/},

doi = {10.1124/jpet.120.000129},

issn = {0022-3565},

year  = {2021},

date = {2021-01-01},

journal = {Journal of Pharmacology and Experimental Therapeutics},

volume = {376},

number = {1},

pages = {118--126},

publisher = {American Society for Pharmacology and Experimental Therapeutics},

abstract = {Dietary supplements often contain additives not listed on the label, including α-ethyl homologs of amphetamine such as N,α-diethylphenethylamine (DEPEA). Here, we examined the neurochemical and cardiovascular effects of α-ethylphenethylamine (AEPEA), N-methyl-α-ethylphenethylamine (MEPEA), and DEPEA as compared with the effects of amphetamine. All drugs were tested in vitro using uptake inhibition and release assays for monoamine transporters. As expected, amphetamine acted as a potent and efficacious releasing agent at dopamine transporters (DAT) and norepinephrine transporters (NET) in vitro. AEPEA and MEPEA were also releasers at catecholamine transporters, with greater potency at NET than DAT. DEPEA displayed fully efficacious release at NET but weak partial release at DAT (i.e., 40% of maximal effect). In freely moving, conscious male rats fitted with biotelemetry transmitters for physiologic monitoring, amphetamine (0.1–3.0 mg/kg, s.c.) produced robust dose-related increases in blood pressure (BP), heart rate (HR), and motor activity. AEPEA (1–10 mg/kg, s.c.) produced significant increases in BP but not HR or activity, whereas DEPEA and MEPEA (1–10 mg/kg, s.c.) increased BP, HR, and activity. In general, the phenethylamine analogs were approximately 10-fold less potent than amphetamine. Our results show that α-ethylphenethylamine analogs are biologically active. Although less potent than amphetamine, they produce cardiovascular effects that could pose risks to humans. Given that MEPEA and DEPEA increased locomotor activity, these substances may also have significant abuse potential.SIGNIFICANCE STATEMENT The α-ethyl homologs of amphetamine have significant cardiovascular, behavioral, and neurochemical effects in rats. Given that these compounds are often not listed on the ingredient labels of dietary supplements, these compounds could pose a risk to humans using these products.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Brandt:2020aa,

title = {The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats},

author = {Simon D Brandt and Hailey M Walters and John S Partilla and Bruce E Blough and Pierce V Kavanagh and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/32875347/},

doi = {10.1007/s00213-020-05648-z},

isbn = {1432-2072},

year  = {2020},

date = {2020-01-01},

journal = {Psychopharmacology},

volume = {237},

number = {12},

pages = {3703--3714},

abstract = {The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called ``benzofury''compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{brainsci10110895,

title = {U-47700 and Its Analogs: Non-Fentanyl Synthetic Opioids Impacting the Recreational Drug Market},

author = {Michael H Baumann and Graziella Tocco and Donna M Papsun and Amanda L Mohr and Melissa F Fogarty and Alex J Krotulski},

url = {https://pubmed.ncbi.nlm.nih.gov/33238449/},

doi = {10.3390/brainsci10110895},

issn = {2076-3425},

year  = {2020},

date = {2020-01-01},

journal = {Brain Sciences},

volume = {10},

number = {11},

abstract = {The recreational use of opioid drugs is a global threat to public health and safety. In particular, an epidemic of opioid overdose fatalities is being driven by illicitly manufactured fentanyl, while novel synthetic opioids (NSOs) are appearing on recreational drug markets as standalone products, adulterants in heroin, or ingredients in counterfeit drug preparations. Trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a prime example of a non-fentanyl NSO that is associated with numerous intoxications and fatalities. Here, we review the medicinal chemistry, preclinical pharmacology, clandestine availability, methods for detection, and forensic toxicology of U-47700 and its analogs. An up-to-date summary of the human cases involving U-47700 intoxication and death are described. The evidence demonstrates that U-47700 is a potent μ-opioid receptor agonist, which poses a serious risk for overdosing and death. However, most analogs of U-47700 appear to be less potent and have been detected infrequently in forensic specimens. U-47700 represents a classic example of how chemical entities from the medicinal chemistry or patent literature can be diverted for use in recreational drug markets. Lessons learned from the experiences with U-47700 can inform scientists, clinicians, and policymakers who are involved with responding to the spread and impact of NSOs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{TRUVER2020108195,

title = {Pharmacodynamics and pharmacokinetics of the novel synthetic opioid, U-47700, in male rats},

author = {Michael T Truver and Christina R Smith and Nancy Garibay and Theresa A Kopajtic and Madeleine J Swortwood and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/32533977/},

doi = {https://doi.org/10.1016/j.neuropharm.2020.108195},

issn = {0028-3908},

year  = {2020},

date = {2020-01-01},

journal = {Neuropharmacology},

volume = {177},

pages = {108195},

abstract = {Novel synthetic opioids are appearing in recreational drug markets worldwide as adulterants in heroin or ingredients in counterfeit analgesic medications. Trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methyl-benzamide (U-47700) is an example of a non-fentanyl synthetic opioid linked to overdose deaths. Here, we examined the pharmacodynamics and pharmacokinetics of U-47700 in rats. Male Sprague-Dawley rats were fitted with intravenous (i.v.) catheters and subcutaneous (s.c.) temperature transponders under ketamine/xylazine anesthesia. One week later, rats received s.c. injections of U-47700 HCl (0.3, 1.0 or 3.0 mg/kg) or saline, and blood samples (0.3 mL) were withdrawn via i.v. catheters at 15, 30, 60, 120, 240, 480 min post-injection. Pharmacodynamic effects were assessed at each blood withdrawal, and plasma was assayed for U-47700 and its metabolites by liquid chromatography tandem mass spectrometry. U-47700 induced dose-related increases in hot plate latency (ED50 = 0.5 mg/kg) and catalepsy (ED50 = 1.7 mg/kg), while the 3.0 mg/kg dose also caused hypothermia. Plasma levels of U-47700 rose linearly as dose increased, with maximal concentration (Cmax) achieved by 15--38 min. Cmax values for N-desmethyl-U-47700 and N,N-didesmethyl-U-47700 were delayed but reached levels in the same range as the parent compound. Pharmacodynamic effects were correlated with plasma U-47700 and its N-desmethyl metabolite. Using radioligand binding assays, U-47700 displayed high affinity for μ-opioid receptors (Ki = 11.1 nM) whereas metabolites were more than 18-fold weaker. Our data reveal that U-47700 induces typical μ-opioid effects which are related to plasma concentrations of the parent compound. Given its high potency, U-47700 poses substantial risk to humans who are inadvertently exposed to the drug.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{https://doi.org/10.1111/adb.12842,

title = {Stereoselective neurochemical, behavioral, and cardiovascular effects of α-pyrrolidinovalerophenone enantiomers in male rats},

author = {Charles W Schindler and Eric B Thorndike and Hailey M Walters and Donna Walther and Kenner C Rice and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/31724254/},

doi = {https://doi.org/10.1111/adb.12842},

year  = {2020},

date = {2020-01-01},

journal = {Addiction Biology},

volume = {25},

number = {6},

pages = {e12842},

abstract = {Abstract The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP) continues to be abused despite being banned by regulatory agencies. The abused formulation of α-PVP is a racemic mixture consisting of two enantiomers, S-α-PVP and R-α-PVP. In this study, we investigated the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP and its enantiomers in male rats. Racemic α-PVP blocked the uptake of both dopamine and norepinephrine ex vivo, but did not block the uptake of serotonin (5-HT), at their respective transporters. S-α-PVP was slightly more potent than racemic α-PVP, while R-α-PVP was 10 to 20 times less potent at blocking dopamine and norepinephrine uptake. In microdialysis studies, racemic and S-α-PVP increased extracellular dopamine levels in the nucleus accumbens, but not levels of 5-HT. Racemic and S-α-PVP also increased locomotor activity. When tested at the same doses, S-α-PVP produced larger effects than racemic α-PVP. R-α-PVP also increased extracellular dopamine levels and locomotor activity, but only at 30 times higher doses than S-α-PVP. Racemic and S-α-PVP were self-administered by rats at 0.03 mg/kg/injection, whereas R-α-PVP was self-administered at a 10 times higher dose. Dose-effect determinations following acquisition suggested that R-α-PVP was at least 30 times less potent than S-α-PVP. Finally, racemic and S-α-PVP increased blood pressure and heart rate at doses approximately 30 times less than was required for R-α-PVP to produce similar effects. These results show that the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP most likely reflect the actions of S isomer.},

note = {e12842 AB-05-2019-0122.R2},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{BERGH2019107596,

title = {Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats},

author = {Marianne Skov-Skov Bergh and Inger Lise Bogen and Nancy Garibay and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/30965021/},

doi = {https://doi.org/10.1016/j.neuropharm.2019.04.002},

issn = {0028-3908},

year  = {2019},

date = {2019-01-01},

journal = {Neuropharmacology},

volume = {158},

pages = {107596},

abstract = {The current opioid overdose crisis is being exacerbated by illicitly manufactured fentanyl and its analogs. Carfentanil is a fentanyl analog that is 10,000-times more potent than morphine, but limited information is available about its pharmacology. The present study had two aims: 1) to validate a method for quantifying carfentanil and its metabolite norcarfentanil in small-volume samples, and 2) to use the method for examining pharmacodynamic-pharmacokinetic relationships in rats. The analytical method involved liquid-liquid extraction of plasma samples followed by quantitation of carfentanil and norcarfentanil using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The method was validated following SWGTOX guidelines, and both analytes displayed limits of detection and quantification at 7.5 and 15 pg/mL, respectively. Male Sprague-Dawley rats fitted with jugular catheters and temperature transponders received subcutaneous carfentanil (1, 3 and 10 μg/kg) or saline. Repeated blood specimens were obtained over 8 h, along with pharmacodynamic measures including core temperature and catalepsy scores. Carfentanil produced dose-related hypothermia and catalepsy that lasted up to 8 h. Carfentanil Cmax occurred at 15 min whereas metabolite Cmax was at 1--2 h. Concentrations of both analytes increased in a dose-related fashion, but area-under-the-curve values were much greater than predicted after 10 μg/kg. Plasma half-life for carfentanil increased at higher doses. Our findings reveal that carfentanil produces marked hypothermia and catalepsy, which is accompanied by nonlinear accumulation of the drug at high doses. We hypothesize that impaired clearance of carfentanil in humans could contribute to life-threatening effects of this ultrapotent opioid agonist. This article is part of the Special Issue entitled `New Vistas in Opioid Pharmacology'.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Halberstadt:2019aa,

title = {2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α_{2}-adrenergic receptors},

author = {Adam L Halberstadt and Simon D Brandt and Donna Walther and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/30904940/},

doi = {10.1007/s00213-019-05207-1},

isbn = {1432-2072},

year  = {2019},

date = {2019-01-01},

journal = {Psychopharmacology},

volume = {236},

number = {3},

pages = {989--999},

abstract = {Over the last decade, many new psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs. Another aminoindan derivative, 5-methoxy-2-aminoindan (5-MeO-AI or MEAI), is the active ingredient in a product marketed online as an alcohol substitute.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Schindler328,

title = {The Supplement Adulterant \textit{β}-Methylphenethylamine Increases Blood Pressure by Acting at Peripheral Norepinephrine Transporters},

author = {Charles W Schindler and Eric B Thorndike and Kenner C Rice and John S Partilla and Michael H Baumann},

url = {https://pubmed.ncbi.nlm.nih.gov/30898867/},

doi = {10.1124/jpet.118.255976},

issn = {0022-3565},

year  = {2019},

date = {2019-01-01},

journal = {Journal of Pharmacology and Experimental Therapeutics},

volume = {369},

number = {3},

pages = {328--336},

publisher = {American Society for Pharmacology and Experimental Therapeutics},

abstract = {β-Methylphenethylamine [(BMPEA), 2-phenylpropan-1-amine] is a structural isomer of amphetamine (1-phenylpropan-2-amine) that has been identified in preworkout and weight loss supplements, yet little information is available about its pharmacology. Here, the neurochemical and cardiovascular effects of BMPEA and its analogs, N-methyl-2-phenylpropan-1-amine (MPPA) and N,N-dimethyl-2-phenylpropan-1-amine (DMPPA), were compared with structurally related amphetamines. As expected, amphetamine and methamphetamine were potent substrate-type releasing agents at dopamine transporters (DATs) and norepinephrine transporters (NETs) in rat brain synaptosomes. BMPEA and MPPA were also substrates at DATs and NETs, but they were at least 10-fold less potent than amphetamine. DMPPA was a weak substrate only at NETs. Importantly, the releasing actions of BMPEA and MPPA were more potent at NETs than DATs. Amphetamine produced significant dose-related increases in blood pressure (BP), heart rate (HR), and locomotor activity in conscious rats fitted with surgically implanted biotelemetry transmitters. BMPEA, MPPA, and DMPPA produced increases in BP that were similar to the effects of amphetamine, but the compounds failed to substantially affect HR or activity. The hypertensive effect of BMPEA was reversed by the α-adrenergic antagonist prazosin but not the ganglionic blocker chlorisondamine. Radioligand binding at various G protein–coupled receptors did not identify nontransporter sites of action that could account for cardiovascular effects of BMPEA or its analogs. Our results show that BMPEA, MPPA, and DMPPA are biologically active. The compounds are unlikely to be abused due to weak effects at DATs, but they could produce adverse cardiovascular effects via substrate activity at peripheral NET sites.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Baumann:2018aa,

title = {Pharmacological Research as a Key Component in Mitigating the Opioid Overdose Crisis},

author = {Michael H Baumann and Theresa A Kopajtic and Bertha K Madras},

url = {https://pubmed.ncbi.nlm.nih.gov/30454770/},

doi = {10.1016/j.tips.2018.09.006},

isbn = {0165-6147},

year  = {2018},

date = {2018-12-01},

booktitle = {Trends in Pharmacological Sciences},

journal = {Trends in Pharmacological Sciences},

volume = {39},

number = {12},

pages = {995--998},

publisher = {Elsevier},

abstract = {The United States is experiencing an epidemic of opioid overdose deaths. Many of the recent fatalities are associated with illicitly manufactured fentanyl, which is being added to heroin and counterfeit pain pills. The crisis is further exacerbated by the emergence of an increasing number of novel synthetic opioids (NSOs), including various fentanyl analogs and non-fentanyl compounds that display potent agonist actions at the ?-opioid receptor. Importantly, most users are unaware of their exposure to fentanyl and NSOs. Stemming the tide of opioid-related fatalities will require a coordinated multidisciplinary response from policy makers, law enforcement personnel, first responders, treatment providers, family members, and scientists. To this end, basic research in pharmacology can contribute significantly to mitigating the crisis through efforts to characterize the biological effects of NSOs, discover more effective antidotes for overdose rescue, and develop safer medications for treating addiction and alleviating pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Elmore:2018ab,

title = {Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats.},

author = {Joshua S Elmore and Ann M Decker and Agnieszka Sulima and Kenner C Rice and John S Partilla and Bruce E Blough and Michael H Baumann},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29501528},

doi = {10.1016/j.neuropharm.2018.02.033},

issn = {1873-7064 (Electronic); 0028-3908 (Linking)},

year  = {2018},

date = {2018-03-01},

journal = {Neuropharmacology},

address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.},

abstract = {2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2A receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT2A receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3mg/kg), 25I-NBOMe (0.01-0.3mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1-3.0mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0mg/kg) and DOI (0.03-1.0mg/kg) were administered subcutaneously (sc) to male rats, and 5-HT2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT2A receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C-I. Pretreatment with the selective 5-HT2A antagonist (R)-(2,3-dimethoxyphenyl)1-[2-(4-fluorophenyl)ethyl]-4-piperidinylmethanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT2A agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Elmore:2018aa,

title = {Repeated Exposure to the "Spice" Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats.},

author = {Joshua S Elmore and Michael H Baumann},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29535650},

doi = {10.3389/fpsyt.2018.00055},

issn = {1664-0640 (Print); 1664-0640 (Linking)},

year  = {2018},

date = {2018-02-27},

journal = {Front Psychiatry},

volume = {9},

pages = {55},

address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, United States.},

abstract = {Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) is a synthetic compound found in psychoactive "spice" products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc) temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc) or its vehicle for seven consecutive days. Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc) or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc), then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks), while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading, and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Schindler:2017aa,

title = {Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats.},

author = {Charles W Schindler and Benjamin R Gramling and Zuzana Justinova and Eric B Thorndike and Michael H Baumann},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28846955},

doi = {10.1016/j.drugalcdep.2017.07.029},

issn = {1879-0046 (Electronic); 0376-8716 (Linking)},

year  = {2017},

date = {2017-10-01},

journal = {Drug Alcohol Depend},

volume = {179},

pages = {387--394},

address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, United States; Preclinical Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, United States. Electronic address: cschind@helix.nih.gov.},

abstract = {BACKGROUND: The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Delta(9)-tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. METHODS: Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. RESULTS: THC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH-018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the alpha1 adrenergic antagonist prazosin. CONCLUSIONS: Our results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Solis:2017aa,

title = {N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability.},

author = {Ernesto Jr Solis and John S Partilla and Farhana Sakloth and Iwona Ruchala and Kathryn L Schwienteck and Louis J De Felice and Jose M Eltit and Richard A Glennon and Stevens S Negus and Michael H Baumann},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28530234},

doi = {10.1038/npp.2017.98},

issn = {1740-634X (Electronic); 0893-133X (Linking)},

year  = {2017},

date = {2017-09-01},

journal = {Neuropsychopharmacology},

volume = {42},

number = {10},

pages = {1950--1961},

address = {In Vivo Electrophysiology Unit, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.},

abstract = {Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability. All 4-MA analogs inhibited uptake at DAT, NET, and SERT, but lengthening the amine substituent from methyl to ethyl, propyl, and butyl produced a stepwise decrease in potency. N-methyl 4-MA was an efficacious substrate-type releaser at DAT that evoked an inward depolarizing current and calcium influx, whereas other analogs did not exhibit these effects. N-methyl and N-ethyl 4-MA were substrates at NET, whereas N-propyl and N-butyl 4-MA were not. All analogs acted as SERT substrates, though N-butyl 4-MA had very weak effects. Intracranial self-stimulation in rats showed that elongating the N-alkyl chain decreased abuse-related effects in vivo that appeared to parallel reductions in DAT activity. Overall, converging lines of evidence show that lengthening the N-alkyl substituent of 4-MA reduces potency to inhibit transporters, eliminates substrate activity at DAT and NET, and decreases abuse liability of the compounds.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Prekupec2017,

title = {Misuse of Novel Synthetic Opioids: A Deadly New Trend. },

author = {Matthew P Prekupec and Peter A Mansky and Michael H Baumann},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28590391},

doi = {10.1097/ADM.0000000000000324},

year  = {2017},

date = {2017-07-15},

journal = {J Addict Med},

volume = {11},

number = {7},

pages = {256--265},

abstract = {Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non-fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone.

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Elmore:2017aa,

title = {Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats.},

author = {Joshua S Elmore and Ora Dillon-Carter and John S Partilla and Kayla N Ellefsen and Marta Concheiro and Masaki Suzuki and Kenner C Rice and Marilyn A Huestis and Michael H Baumann},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27658484},

doi = {10.1038/npp.2016.213},

issn = {1740-634X (Electronic); 0893-133X (Linking)},

year  = {2017},

date = {2017-02-01},

journal = {Neuropsychopharmacology},

volume = {42},

number = {3},

pages = {649--660},

address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.},

abstract = {3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the beta-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of methylone and its metabolites after subcutaneous (sc) methylone administration (3, 6, 12 mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that methylone and MDC peaked early (Tmax=15-45 min) and were short lived (t1/2=60-90 min), while HHMC and HMMC peaked later (Tmax=60-120 min) and persisted (t1/2=120-180 min). Area-under-the-curve values for methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only methylone and MDC (1, 3 mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Schindler:2016ab,

title = {Pharmacological mechanisms underlying the cardiovascular effects of the "bath salt" constituent 3,4-methylenedioxypyrovalerone (MDPV).},

author = {Charles W Schindler and Eric B Thorndike and Masaki Suzuki and Kenner C Rice and Michael H Baumann},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27714779},

doi = {10.1111/bph.13640},

issn = {1476-5381 (Electronic); 0007-1188 (Linking)},

year  = {2016},

date = {2016-12-01},

journal = {Br J Pharmacol},

volume = {173},

number = {24},

pages = {3492--3501},

address = {Preclinical Pharmacology Section, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD.},

abstract = {BACKGROUND AND PURPOSE: 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with stimulatory cardiovascular effects that can lead to serious medical complications. Here, we examined the pharmacological mechanisms underlying these cardiovascular actions of MDPV in conscious rats. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats had telemetry transmitters surgically implanted for the measurement of BP and heart rate (HR). On test days, rats were placed individually in standard isolation cubicles. Following drug treatment, cardiovascular parameters were monitored for 3 h sessions. KEY RESULTS: Racemic MDPV (0.3-3.0 mg.kg(-1) ) increased BP and HR in a dose-dependent manner. The S(+) enantiomer (0.3-3.0 mg.kg(-1) ) of MDPV produced similar effects, while the R(-) enantiomer (0.3-3.0 mg.kg(-1) ) had no effects. Neither of the hydroxylated phase I metabolites of MDPV altered cardiovascular parameters significantly from baseline. Pretreatment with the ganglionic blocker chlorisondamine (1 and 3 mg.kg(-1) ) antagonized the increases in BP and HR produced by 1 mg.kg(-1) MDPV. The alpha1 -adrenoceptor antagonist prazosin (0.3 mg.kg(-1) ) attenuated the increase in BP following MDPV, while the beta-adrenoceptor antagonists propranolol (1 mg.kg(-1) ) and atenolol (1 and 3 mg.kg(-1) ) attenuated the HR increases. CONCLUSIONS AND IMPLICATIONS: The S(+) enantiomer appeared to mediate the cardiovascular effects of MDPV, while the metabolites of MDPV did not alter BP or HR significantly; MDPV increased BP and HR through activation of central sympathetic outflow. Mixed-action alpha/beta-adrenoceptor antagonists may be useful as treatments in counteracting the adverse cardiovascular effects of MDPV.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Mayer:2016aa,

title = {Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters.},

author = {F P Mayer and L Wimmer and O Dillon-Carter and J S Partilla and N V Burchardt and M D Mihovilovic and M H Baumann and H H Sitte},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27391165},

doi = {10.1111/bph.13547},

issn = {1476-5381 (Electronic); 0007-1188 (Linking)},

year  = {2016},

date = {2016-09-01},

journal = {Br J Pharmacol},

volume = {173},

number = {17},

pages = {2657--2668},

address = {Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.},

abstract = {BACKGROUND AND PURPOSE: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. EXPERIMENTAL APPROACH: We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3 mg.kg(-1) ) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. KEY RESULTS: In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood-brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Schindler:2016aa,

title = {Reinforcing and neurochemical effects of the "bath salts" constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats.},

author = {Charles W Schindler and Eric B Thorndike and Steven R Goldberg and Kurt R Lehner and Nicholas V Cozzi and Simon D Brandt and Michael H Baumann},

url = {https://www.ncbi.nlm.nih.gov/pubmed/26319160},

doi = {10.1007/s00213-015-4057-0},

issn = {1432-2072 (Electronic); 0033-3158 (Linking)},

year  = {2016},

date = {2016-05-01},

journal = {Psychopharmacology (Berl)},

volume = {233},

number = {10},

pages = {1981--1990},

address = {Preclinical Pharmacology Section, Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA. cschind@helix.nih.gov.},

abstract = {RATIONALE: 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called "bath salts" products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT). OBJECTIVES: We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. METHODS: To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. RESULTS: MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. In contrast, methylone self-administration (0.3 and 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. CONCLUSIONS: Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats, suggesting these drugs possess significant abuse liability in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Marusich:2016aa,

title = {The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue.},

author = {Julie A Marusich and Kateland R Antonazzo and Bruce E Blough and Simon D Brandt and Pierce V Kavanagh and John S Partilla and Michael H Baumann},

url = {https://www.ncbi.nlm.nih.gov/pubmed/26362361},

doi = {10.1016/j.neuropharm.2015.09.004},

issn = {1873-7064 (Electronic); 0028-3908 (Linking)},

year  = {2016},

date = {2016-02-01},

journal = {Neuropharmacology},

volume = {101},

pages = {68--75},

address = {Center for Drug Discovery, RTI International, 3040 Cornwallis Rd, Research Triangle Park, NC 27709, USA. Electronic address: jmarusich@rti.org.},

abstract = {In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}