Amy Hauck Newman, Ph.D.

@article{pmid39237617,

title = {A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site},

author = {Sandra Arroyo-Urea and Antonina L Nazarova and Ángela Carrión-Antolí and Alessandro Bonifazi and Francisco O Battiti and Jordy Homing Lam and Amy Hauck Newman and Vsevolod Katritch and Javier García-Nafría},

url = {https://pubmed.ncbi.nlm.nih.gov/39237617/},

doi = {10.1038/s41467-024-51993-4},

issn = {2041-1723},

year  = {2024},

date = {2024-09-01},

urldate = {2024-09-01},

journal = {Nat Commun},

volume = {15},

number = {1},

pages = {7759},

abstract = {Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hDR:Gαβγ complex bound to the DR selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38838841,

title = {Presynaptic and Postsynaptic Mesolimbic Dopamine D_{3} Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice},

author = {Zheng-Xiong Xi and Miriam E Bocarsly and Ewa Galaj and Briana Hempel and Catherine Teresi and Marlisa Shaw and Guo-Hua Bi and Chloe Jordan and Emily Linz and Hannah Alton and Gianluigi Tanda and Zachary Freyberg and Veronica A Alvarez and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/38838841/},

doi = {10.1016/j.biopsych.2024.05.020},

issn = {1873-2402},

year  = {2024},

date = {2024-06-01},

urldate = {2024-06-01},

journal = {Biol Psychiatry},

abstract = {Background: Past research has illuminated pivotal roles of dopamine D3 receptors (D_{3}R) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear.



Methods: We employed Cre-LoxP techniques to selectively delete D_{3}R from presynaptic dopamine neurons or postsynaptic dopamine D_{1} receptor (D_{1}R)-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, real-time polymerase chain reaction, voltammetry, optogenetics, microdialysis, and behavioral assays (n ≥ 8 animals per group) to functionally characterize the roles of presynaptic versus postsynaptic D_{3}R in cocaine and opioid actions.



Results: Our results revealed D_{3}R expression in ∼25% of midbrain dopamine neurons and ∼70% of D_{1}R-expressing neurons in the nucleus accumbens. While dopamine D_{2} receptors (D_{2}R) were expressed in ∼80% dopamine neurons, we found no D_{2}R and D_{3}R colocalization among these cells. Selective deletion of D_{3}R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D_{3}R from D_{1}R-expressing neurons attenuated locomotor responses to D_{1}-like and D_{2}-like agonists. Strikingly, deletion of D_{3}R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D_{3}R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D_{3}R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D_{1}R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia.



Conclusions: We dissected presynaptic versus postsynaptic D_{3}R function in the mesolimbic dopamine system. D_{2}R and D_{3}R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D_{3}R are critically involved in the actions of opioids but not cocaine.



Keywords: Cocaine; Conditional D(3) receptor knockout; Dopamine D(3) receptor; Opioid; Optical brain stimulation reward; Self-administration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38425927,

title = {Development of a Fluorescently Labeled Ligand for Rapid Detection of DAT in Human and Mouse Peripheral Blood Monocytes},

author = {Gisela Andrea Camacho-Hernandez and Adithya Gopinath and Amarachi V Okorom and Habibeh Khoshbouei and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/38425927/},

doi = {10.1021/jacsau.3c00719},

issn = {2691-3704},

year  = {2024},

date = {2024-02-01},

urldate = {2024-02-01},

journal = {JACS Au},

volume = {4},

number = {2},

pages = {657--665},

abstract = {The dopamine transporter (DAT) is one of the key regulators of dopamine (DA) signaling in the central nervous system (CNS) and in the periphery. Recent reports in a model of Parkinson's disease (PD) have shown that dopamine neuronal loss in the CNS impacts the expression of DAT in peripheral immune cells. The mechanism underlying this connection is still unclear but could be illuminated with sensitive and high-throughput detection of DAT-expressing immune cells in the circulation. Herein, we have developed fluorescently labeled ligands (FLL) that bind to surface-expressing DAT with high affinity and selectivity. The diSulfoCy5-FLL () was utilized to label DAT in human and mouse peripheral blood mononuclear cells (PBMCs) that were analyzed via flow cytometry. Selective labeling was validated using DAT KO mouse PBMCs. Our studies provide an efficient and highly sensitive method using this novel DAT-selective FLL to advance our fundamental understanding of DAT expression and activity in PBMCs in health and disease and as a potential peripheral biomarker.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37467430,

title = {Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D_{3} (D_{3}R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics},

author = {Alessandro Bonifazi and Elizabeth Saab and Julie Sanchez and Antonina L Nazarova and Saheem A Zaidi and Khorshada Jahan and Vsevolod Katritch and Meritxell Canals and J Robert Lane and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/37467430/},

doi = {10.1021/acs.jmedchem.3c00417},

issn = {1520-4804},

year  = {2023},

date = {2023-08-01},

urldate = {2023-08-01},

journal = {J Med Chem},

volume = {66},

number = {15},

pages = {10304--10341},

abstract = {A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D receptor (DR) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity screening, in silico computer-aided drug design, and BRET functional assays, we identified new structural scaffolds that achieved high affinity and agonist/antagonist potencies for MOR and DR, respectively, improving the dopamine receptor subtype selectivity (e.g., DR over DR) and significantly enhancing central nervous system multiparameter optimization scores for predicted blood-brain barrier permeability. We identified the substituted -(2,4)-pyrrolidine and -phenylcyclopropyl amine as key dopaminergic moieties and tethered these to different opioid scaffolds, derived from the MOR agonists  () or loperamide (). The lead compounds , ,  and  have the potential of producing analgesic effects through MOR partial agonism with reduced opioid-misuse liability via DR antagonism. Moreover, the peripherally limited derivatives could have therapeutic indications for inflammation and neuropathic pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Gogarnoiu:2023aa,

title = {Dopamine D_{3}/D_{2} Receptor Ligands Based on Cariprazine for the Treatment of Psychostimulant Use Disorders That May Be Dual Diagnosed with Affective Disorders},

author = {Emma S. Gogarnoiu and Caleb D. Vogt and Julie Sanchez and Alessandro Bonifazi and Elizabeth Saab and Anver Basha Shaik and Omar Soler-Cedeño and Guo-Hua Bi and Benjamin Klein and Zheng-Xiong Xi and J. Robert Lane and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/36661568/},

doi = {10.1021/acs.jmedchem.2c01624},

isbn = {0022-2623},

year  = {2023},

date = {2023-01-20},

urldate = {2023-01-20},

journal = {Journal of Medicinal Chemistry},

volume = {66},

number = {3},

pages = {1809–1834},

publisher = {American Chemical Society},

abstract = {Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have been developed for the treatment of psychostimulant use disorders (PSUD). However, none have reached the clinic due to insufficient potency/efficacy or potential cardiotoxicity. Cariprazine, an FDA-approved drug for the treatment of schizophrenia and bipolar disorder, is a high-affinity D3R partial agonist (Ki = 0.22 nM) with 3.6-fold selectivity over the homologous dopamine D2 receptor (D2R). We hypothesized that compounds that are moderately D3R/D2R-selective partial agonists/antagonists may be effective for the treatment of PSUD. By systematically modifying the parent molecule, we discovered partial agonists/antagonists, as measured in bioluminescence resonance energy transfer (BRET)-based assays, with high D3R affinities (Ki = 0.14–50 nM) and moderate selectivity (<100-fold) over D2R. Cariprazine and two lead analogues, 13a and 13e, decreased cocaine self-administration (FR2; 1–10 mg/kg, i.p.) in rats, suggesting that partial agonists/antagonists with modest D3R/D2R selectivity may be effective in treating PSUD and potentially comorbidities with other affective disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35543868,

title = {Current Perspectives on Selective Dopamine D Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psychostimulant Use Disorders},

author = {Amy Hauck Newman and Zheng-Xiong Xi and Christian Heidbreder},

url = {https://pubmed.ncbi.nlm.nih.gov/35543868/},

doi = {10.1007/7854_2022_347},

issn = {1866-3370},

year  = {2023},

date = {2023-01-01},

urldate = {2023-01-01},

journal = {Curr Top Behav Neurosci},

volume = {60},

pages = {157--201},

abstract = {Over three decades of evidence indicate that dopamine (DA) D receptors (DR) are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders (SUD). The expectation that a selective DR antagonist/partial agonist would be efficacious for the treatment of SUD is based on the following key observations. First, DR are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and ventral pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse produces neuroadaptations in the DR system. Third, the synthesis and characterization of highly potent and selective DR antagonists/partial agonists have further strengthened the role of the DR in SUD. Based on extensive preclinical and preliminary clinical evidence, the DR shows promise as a target for the development of pharmacotherapies for SUD as reflected by their potential to (1) regulate the motivation to self-administer drugs and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, drug-associated environmental cues, or stress. The availability of PET ligands to assess clinically relevant receptor occupancy by selective DR antagonists/partial agonists, the definition of reliable dosing, and the prospect of using human laboratory models may further guide the design of clinical proof of concept studies. Pivotal clinical trials for more rapid progression of this target toward regulatory approval are urgently required. Finally, the discovery that highly selective DR antagonists, such as R-VK4-116 and R-VK4-40, do not adversely affect peripheral biometrics or cardiovascular effects alone or in the presence of oxycodone or cocaine suggests that this class of drugs has great potential in safely treating psychostimulant and/or opioid use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35879349,

title = {A highly D_{3}R-selective and efficacious partial agonist (S)-ABS01-113 compared to its DR-selective antagonist enantiomer (R)-ABS01-113 as potential treatments for opioid use disorder},

author = {Ewa Galaj and Guo-Hua Bi and Benjamin Klein and Briana Hempel and Anver Basha Shaik and Emma S Gogarnoiu and Jacob Friedman and Jenny Lam and Rana Rais and John F Reed and Shelley H Bloom and Tracy L Swanson and Jennifer L Schmachtenberg and Amy J Eshleman and Aaron Janowsky and Zheng-Xiong Xi and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/35879349/},

doi = {10.1038/s41386-022-01379-1},

issn = {1740-634X},

year  = {2022},

date = {2022-12-01},

urldate = {2022-12-01},

journal = {Neuropsychopharmacology},

volume = {47},

number = {13},

pages = {2309--2318},

abstract = {The non-medical use of opioids has become a national crisis in the USA. Developing non-opioid pharmacotherapies for controlling this opioid epidemic is urgent. Dopamine D receptor (DR) antagonists and low efficacy partial agonists have shown promising profiles in animal models of opioid use disorders (OUD). However, to date, advancement to human studies has been limited. Here we report the effects of (S)- and (R)-enantiomers of (±)-ABS01-113, structural analogs of the DR partial agonist, (±)-VK4-40, in which the 3-OH in the linking chain is replaced by 3-F group. (S)- and (R)-ABS01-113 are identical in chemical structure but with opposite chirality. In vitro receptor binding and functional assays indicate that (S)-ABS01-113 is an efficacious (55%) and potent (EC = 7.6 ± 3.9 nM) DR partial agonist, while the (R)-enantiomer is a potent DR antagonist (IC = 11.4 nM). Both (S)- and (R)-ABS01-113 bind with high affinity to DR (K = 0.84 ± 0.16 and 0.37 ± 0.06 nM, respectively); however, the (S)-enantiomer is more D/D-selective (>1000-fold). Pharmacokinetic analyses indicate that both enantiomers display excellent oral bioavailability and high brain penetration. Systemic administration of (S)- or (R)-ABS01-113 alone failed to alter open-field locomotion in male rats and mice. Interestingly, pretreatment with (S)- or (R)-ABS01-113 attenuated heroin-enhanced hyperactivity, heroin self-administration, and (heroin + cue)-induced reinstatement of drug-seeking behavior. Together, these findings reveal that both enantiomers, particularly the highly selective and efficacious DR partial agonist (S)-ABS01-113, demonstrate promising translational potential for the treatment of OUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36527444,

title = {Illuminating the monoamine transporters: Fluorescently labelled ligands to study dopamine, serotonin and norepinephrine transporters},

author = {Gisela Andrea Camacho-Hernandez and Khorshada Jahan and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/36527444/},

doi = {10.1111/bcpt.13827},

issn = {1742-7843},

year  = {2022},

date = {2022-12-01},

urldate = {2022-12-01},

journal = {Basic Clin Pharmacol Toxicol},

abstract = {Fluorescence microscopy has revolutionized the visualization of physiological processes in live-cell systems. With the recent innovations in super resolution microscopy, these events can be examined with high precision and accuracy. The development of fluorescently labelled small molecules has provided a significant advance in understanding the physiological relevance of targeted proteins that can now be visualized at the cellular level. One set of physiologically important target proteins are the monoamine transporters (MATs) that play an instrumental role in maintaining monoamine signalling homeostasis. Understanding the mechanisms underlying their regulation and dysregulation is fundamental to treating several neuropsychiatric conditions such as attention deficit hyperactivity disorder (ADHD), anxiety, depression and substance use disorders. Herein, we describe the rationale behind the small molecule design of fluorescently labelled ligands (FLL) either as MAT substrates or inhibitors as well as their applications to advance our understanding of this class of transporters in health and disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35931070,

title = {Synaptic-like axo-axonal transmission from striatal cholinergic interneurons onto dopaminergic fibers},

author = {Paul F Kramer and Samuel G Brill-Weil and Alex C Cummins and Renshu Zhang and Gisela A Camacho-Hernandez and Amy Hauck Newman and Mark A G Eldridge and Bruno B Averbeck and Zayd M Khaliq},

url = {https://pubmed.ncbi.nlm.nih.gov/35931070/},

doi = {10.1016/j.neuron.2022.07.011},

issn = {1097-4199},

year  = {2022},

date = {2022-08-01},

urldate = {2022-08-01},

journal = {Neuron},

abstract = {Transmission from striatal cholinergic interneurons (CINs) controls dopamine release through nicotinic acetylcholine receptors (nAChRs) on dopaminergic axons. Anatomical studies suggest that cholinergic terminals signal predominantly through non-synaptic volume transmission. However, the influence of cholinergic transmission on electrical signaling in axons remains unclear. We examined axo-axonal transmission from CINs onto dopaminergic axons using perforated-patch recordings, which revealed rapid spontaneous EPSPs with properties characteristic of fast synapses. Pharmacology showed that axonal EPSPs (axEPSPs) were mediated primarily by high-affinity α6-containing receptors. Remarkably, axEPSPs triggered spontaneous action potentials, suggesting that these axons perform integration to convert synaptic input into spiking, a function associated with somatodendritic compartments. We investigated the cross-species validity of cholinergic axo-axonal transmission by recording dopaminergic axons in macaque putamen and found similar axEPSPs. Thus, we reveal that synaptic-like neurotransmission underlies cholinergic signaling onto dopaminergic axons, supporting the idea that striatal dopamine release can occur independently of somatic firing to provide distinct signaling.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34355183,

title = {Illuminating the norepinephrine transporter: fluorescent probes based on nisoxetine and talopram},

author = {Gisela Andrea Camacho-Hernandez and Andrea Casiraghi and Deborah Rudin and Dino Luethi and Therese C Ku and Daryl A Guthrie and Valentina Straniero and Ermanno Valoti and Gerhard J Schütz and Harald H Sitte and Amy Hauck Newman},

doi = {10.1039/d1md00072a},

issn = {2632-8682},

year  = {2021},

date = {2021-07-01},

urldate = {2021-07-01},

journal = {RSC Med Chem},

volume = {12},

number = {7},

pages = {1174--1186},

abstract = {The utilization of fluorescent ligands to study the monoamine transporters (MATs) has increased our knowledge of their function and distribution in live cell systems. In this study, we extend SAR for nisoxetine and talopram as parent compounds, to identify high affinity rhodamine-labeled fluorescent probes for the norepinephrine transporter (NET). Nisoxetine-based fluorescent probe  demonstrated high binding affinity (  = 43 nM) for NET and an overall selectivity compared to the other transporters for dopamine (DAT;   = 1540 nM) and serotonin (SERT;   = 785 nM) in competitive radioligand binding assays. Using confocal microscopy, compound  was shown to stain both NET and SERT, but not DAT, at low nanomolar concentrations, in transporter-expressing cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33411583b,

title = {New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders},

author = {Amy Hauck Newman and Therese Ku and Chloe J Jordan and Alessandro Bonifazi and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/33411583/},

doi = {10.1146/annurev-pharmtox-030220-124205},

issn = {1545-4304},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Annu Rev Pharmacol Toxicol},

volume = {61},

pages = {609--628},

abstract = {The abuse of illicit psychostimulants such as cocaine and methamphetamine continues to pose significant health and societal challenges. Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions about what mechanism(s) of action should be targeted for developing pharmacotherapies. As both cocaine and methamphetamine rapidly increase dopamine (DA) levels in mesolimbic brain regions, leading to euphoria that in some can lead to addiction, targets in which this increased dopaminergic tone may be mitigated have been explored. Further, understanding and targeting mechanisms underlying relapse are fundamental to the success of discovering medications that reduce the reinforcing effects of the drug of abuse, decrease the negative reinforcement or withdrawal/negative affect that occurs during abstinence, or both. Atypical inhibitors of the DA transporter and partial agonists/antagonists at DA D receptors are described as two promising targets for future drug development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34011153,

title = {Novel Dual-Target μ-Opioid Receptor and Dopamine D_{3} Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management},

author = {Alessandro Bonifazi and Francisco O Battiti and Julie Sanchez and Saheem A Zaidi and Eric Bow and Mariia Makarova and Jianjing Cao and Anver Basha Shaik and Agnieszka Sulima and Kenner C Rice and Vsevolod Katritch and Meritxell Canals and J Robert Lane and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/34355183/},

doi = {10.1021/acs.jmedchem.1c00611},

issn = {1520-4804},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {J Med Chem},

volume = {64},

number = {11},

pages = {7778--7808},

abstract = {The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D receptor (DR) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the DR as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and DR. Structure-activity relationship studies using computationally aided drug design and  binding assays led to the identification of potent dual-target leads (, , and ), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist-DR antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34636551,

title = {Structure Activity Relationships for a Series of Eticlopride-Based Dopamine D_{2}/D_{3} Receptor Bitopic Ligands.},

author = {Anver Basha Shaik and Comfort A Boateng and Francisco O Battiti and Alessandro Bonifazi and Jianjing Cao and Li Chen and Rezvan Chitsazi and Saiprasad Ravi and Kuo Hao Lee and Lei Shi and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/34636551/},

doi = {10.1021/acs.jmedchem.1c01353},

issn = {1520-4804},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {J Med Chem},

volume = {64},

number = {20},

pages = {15313--15333},

abstract = {The crystal structure of the dopamine D receptor (DR) in complex with eticlopride inspired the design of bitopic ligands that explored (1) -alkylation of the eticlopride's pyrrolidine ring, (2) shifting of the position of the pyrrolidine nitrogen, (3) expansion of the pyrrolidine ring system, and (4) incorporation of -alkylations at the 4-position. Structure activity relationships (SAR) revealed that moving the - or expanding the pyrrolidine ring was detrimental to DR/DR binding affinities. Small pyrrolidine -alkyl groups were poorly tolerated, but the addition of a linker and secondary pharmacophore (SP) improved affinities. Moreover, -alkylated analogues showed higher binding affinities compared to analogously -alkylated compounds, e.g., -alkylated  (DR, 0.436 nM and DR, 1.77 nM) vs the -alkylated  (DR, 6.97 nM and DR, 25.3 nM). All lead molecules were functional DR/DR antagonists. Molecular models confirmed that 4-position modifications would be well-tolerated for future DR/DR bioconjugate tools that require long linkers and or sterically bulky groups.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Guthrie:2020aa,

title = {Novel Fluorescent Ligands Enable Single-Molecule Localization Microscopy of the Dopamine Transporter},

author = {Daryl A Guthrie and Carmen Klein Herenbrink and Matthew Domenic Lycas and Therese Ku and Alessandro Bonifazi and Brian T DeVree and Signe Mathiasen and Jonathan A Javitch and Jonathan B Grimm and Luke Lavis and Ulrik Gether and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/32926777/},

doi = {10.1021/acschemneuro.0c00397},

year  = {2020},

date = {2020-10-21},

booktitle = {ACS Chemical Neuroscience},

journal = {ACS Chemical Neuroscience},

volume = {11},

number = {20},

pages = {3288--3300},

publisher = {American Chemical Society},

abstract = {The dopamine transporter (DAT) is critical for spatiotemporal control of dopaminergic neurotransmission and is the target for therapeutic agents, including ADHD medications, and abused substances, such as cocaine. Here, we develop new fluorescently labeled ligands that bind DAT with high affinity and enable single-molecule detection of the transporter. The cocaine analogue MFZ2-12 (1) was conjugated to novel rhodamine-based Janelia Fluorophores (JF549 and JF646). High affinity binding of the resulting ligands to DAT was demonstrated by potent inhibition of $[$3H$]$dopamine uptake in DAT transfected CAD cells and by competition radioligand binding experiments on rat striatal membranes. Visualization of binding was substantiated by confocal or TIRF microscopy revealing selective binding of the analogues to DAT transfected CAD cells. Single particle tracking experiments were performed with JF549-conjugated DG3-80 (3) and JF646-conjugated DG4-91 (4) on DAT transfected CAD cells enabling quantification and categorization of the dynamic behavior of DAT into four distinct motion classes (immobile, confined, Brownian, and directed). Finally, we show that the ligands can be used in direct stochastic optical reconstruction microscopy (dSTORM) experiments permitting further analyses of DAT distribution on the nanoscale. In summary, these novel fluorescent ligands are promising new tools for studying DAT localization and regulation with single-molecule resolution.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Battiti:2020aa,

title = {Exception That Proves the Rule: Investigation of Privileged Stereochemistry in Designing Dopamine D3R Bitopic Agonists},

author = {Francisco O Battiti and Amy Hauck Newman and Alessandro Bonifazi},

url = {https://pubmed.ncbi.nlm.nih.gov/33062179/},

doi = {10.1021/acsmedchemlett.9b00660},

year  = {2020},

date = {2020-10-08},

booktitle = {ACS Medicinal Chemistry Letters},

journal = {ACS Medicinal Chemistry Letters},

volume = {11},

number = {10},

pages = {1956--1964},

publisher = {American Chemical Society},

abstract = {In this study, starting from our selective D3R agonist FOB02-04A (5), we investigated the chemical space around the linker portion of the molecule via insertion of a hydroxyl substituent and ring-expansion of the trans-cyclopropyl moiety into a trans-cyclohexyl scaffold. Moreover, to further elucidate the importance of the primary pharmacophore stereochemistry in the design of bitopic ligands, we investigated the chiral requirements of (+)-PD128907 ((+)-(4aR,10bR)-2)) by synthesizing and resolving bitopic analogues in all the cis and trans combinations of its 9-methoxy-3,4,4a,10b-tetrahydro-2H,5H-chromeno$[$4,3-b$]$$[$1,4$]$ oxazine scaffold. Despite the lack of success in obtaining new analogues with improved biological profiles, in comparison to our current leads, a ``negative''result due to a poor or simply not improved biological profile is fundamental toward better understanding chemical space and optimal stereochemistry for target recognition. Herein, we identified essential structural information to understand the differences between orthosteric and bitopic ligand--receptor binding interactions, discriminate D3R active and inactive states, and assist multitarget receptor recognition. Exploring stereochemical complexity and developing extended D3R SAR from this new library complements previously described SAR and inspires future structural and computational biology investigation. Moreover, the expansion of chemical space characterization for D3R agonism may be utilized in machine learning and artificial intelligence (AI)-based drug design, in the future.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{GALAJ202038,

title = {Dopamine D3 receptor-based medication development for the treatment of opioid use disorder: Rationale, progress, and challenges},

author = {Ewa Galaj and Amy Hauck Newman and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/32376243/},

doi = {https://doi.org/10.1016/j.neubiorev.2020.04.024},

issn = {0149-7634},

year  = {2020},

date = {2020-01-01},

journal = {Neuroscience & Biobehavioral Reviews},

volume = {114},

pages = {38 - 52},

abstract = {Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the current national opioid crisis. Although several opioid-based pharmacotherapies are available (e.g., methadone, buprenorphine, naloxone), they show limited effectiveness in long-term relapse prevention. In response to the opioid crisis, the National Institute on Drug Abuse proposed a list of pharmacological targets of highest priority for medication development for the treatment of opioid use disorders (OUD). Among these are antagonists of dopamine D3 receptors (D3R). In this review, we first review recent progress in research of the dopamine hypothesis of opioid reward and abuse and then describe the rationale and recent development of D3R ligands for the treatment of OUD. Herein, an emphasis is placed on the effectiveness of newly developed D3R antagonists in the animal models of OUD. These new drug candidates may also potentiate the analgesic effects of clinically used opioids, making them attractive as adjunctive medications for pain management and treatment of OUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Battiti:2019aa,

title = {The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as D3 Receptor (D3R) Selective Agonists.},

author = {Francisco O Battiti and Sophie L Cemaj and Adrian M Guerrero and Anver Basha Shaik and Jenny Lam and Rana Rais and Barbara S Slusher and Jeffery R Deschamps and Greg H Imler and Amy Hauck Newman and Alessandro Bonifazi},

url = {https://www.ncbi.nlm.nih.gov/pubmed/31257877},

doi = {10.1021/acs.jmedchem.9b00702},

issn = {1520-4804 (Electronic); 0022-2623 (Linking)},

year  = {2019},

date = {2019-07-11},

journal = {J Med Chem},

volume = {62},

number = {13},

pages = {6287--6314},

address = {Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program , National Institutes of Health , 333 Cassell Drive , Baltimore , Maryland 21224 , United States.},

abstract = {Because of the large degree of homology among dopamine D2-like receptors, discovering ligands capable of discriminating between the D2, D3, and D4 receptor subtypes remains a significant challenge. Previous work has exemplified the use of bitopic ligands as a powerful strategy in achieving subtype selectivity for agonists and antagonists alike. Inspired by the potential for chemical modification of the D3 preferential agonists (+)-PD128,907 (1) and PF592,379 (2), we synthesized bitopic structures to further improve their D3R selectivity. We found that the (2S,5S) conformation of scaffold 2 resulted in a privileged architecture with increased affinity and selectivity for the D3R. In addition, a cyclopropyl moiety incorporated into the linker and full resolution of the chiral centers resulted in lead compound 53 and eutomer 53a that demonstrate significantly higher D3R binding selectivities than the reference compounds. Moreover, the favorable metabolic stability in rat liver microsomes supports future studies in in vivo models of dopamine system dysregulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Newman:2019aa,

title = {Translating the atypical dopamine uptake inhibitor hypothesis toward therapeutics for treatment of psychostimulant use disorders.},

author = {Amy Hauck Newman and Jianjing Cao and Jacqueline D Keighron and Chloe J Jordan and Guo-Hua Bi and Ying Liang and Ara M Abramyan and Alicia J Avelar and Christopher W Tschumi and Michael J Beckstead and Lei Shi and Gianluigi Tanda and Zheng-Xiong Xi},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30858517},

doi = {10.1038/s41386-019-0366-z},

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

year  = {2019},

date = {2019-07-01},

journal = {Neuropsychopharmacology},

volume = {44},

number = {8},

pages = {1435--1444},

address = {Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD, 21224, USA. anewman@intra.nida.nih.gov.},

abstract = {Medication-assisted treatments are unavailable to patients with cocaine use disorders. Efforts to develop potential pharmacotherapies have led to the identification of a promising lead molecule, JJC8-091, that demonstrates a novel binding mode at the dopamine transporter (DAT). Here, JJC8-091 and a structural analogue, JJC8-088, were extensively and comparatively assessed to elucidate neurochemical correlates to their divergent behavioral profiles. Despite sharing significant structural similarity, JJC8-088 was more cocaine-like, increasing extracellular DA concentrations in the nucleus accumbens shell (NAS) efficaciously and more potently than JJC8-091. In contrast, JJC8-091 was not self-administered and was effective in blocking cocaine-induced reinstatement to drug seeking. Electrophysiology experiments confirmed that JJC8-091 was more effective than JJC8-088 at inhibiting cocaine-mediated enhancement of DA neurotransmission. Further, when VTA DA neurons in DAT-cre mice were optically stimulated, JJC8-088 produced a significant leftward shift in the stimulation-response curve, similar to cocaine, while JJC8-091 shifted the curve downward, suggesting attenuation of DA-mediated brain reward. Computational models predicted that JJC8-088 binds in an outward facing conformation of DAT, similar to cocaine. Conversely, JJC8-091 steers DAT towards a more occluded conformation. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of cocaine use disorders, with JJC8-091 representing a compelling candidate for development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bonifazi:2019aa,

title = {Novel and Potent Dopamine D2 Receptor Go-Protein Biased Agonists.},

author = {Alessandro Bonifazi and Hideaki Yano and Adrian M Guerrero and Vivek Kumar and Alexander F Hoffman and Carl R Lupica and Lei Shi and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30775693},

doi = {10.1021/acsptsci.8b00060},

issn = {2575-9108 (Electronic); 2575-9108 (Linking)},

year  = {2019},

date = {2019-02-08},

journal = {ACS Pharmacol Transl Sci},

volume = {2},

number = {1},

pages = {52--65},

address = {Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.},

abstract = {The discovery of functionally biased and physiologically beneficial ligands directed toward G-protein coupled receptors (GPCRs) has provided the impetus to design dopamine D2 receptor (D2R) targeted molecules that may be therapeutically advantageous for the treatment of certain neuropsychiatric or basal ganglia related disorders. Here we describe the synthesis of a novel series of D2R agonists linking the D2R unbiased agonist sumanirole with privileged secondary molecular fragments. The resulting ligands demonstrate improved D2R affinity and selectivity over sumanirole. Extensive in vitro functional studies and bias factor analysis led to the identification of a novel class of highly potent Go-protein biased full D2R agonists with more than 10-fold and 1000-fold bias selectivity toward activation of specific G-protein subtypes and beta-arrestin, respectively. Intracellular electrophysiological recordings from midbrain dopamine neurons demonstrated that Go-protein selective agonists can elicit prolonged ligand-induced GIRK activity via D2Rs, which may be beneficial in the treatment of dyskinesias associated with dopamine system dysfunction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{You:2018aa,

title = {Dopamine D3R antagonist VK4-116 attenuates oxycodone self-administration and reinstatement without compromising its antinociceptive effects.},

author = {Zhi-Bing You and Guo-Hua Bi and Ewa Galaj and Vivek Kumar and Jianjing Cao and Alexandra Gadiano and Rana Rais and Barbara S Slusher and Eliot L Gardner and Zheng-Xiong Xi and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30555159},

doi = {10.1038/s41386-018-0284-5},

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

year  = {2018},

date = {2018-11-27},

journal = {Neuropsychopharmacology},

address = {Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, 21224, USA.},

abstract = {Prescription opioids such as oxycodone are highly effective analgesics for clinical pain management, but their misuse and abuse have led to the current opioid epidemic in the United States. In order to ameliorate this public health crisis, the development of effective pharmacotherapies for the prevention and treatment of opioid abuse and addiction is essential and urgently required. In this study, we evaluated-in laboratory rats-the potential utility of VK4-116, a novel and highly selective dopamine D3 receptor (D3R) antagonist, for the prevention and treatment of prescription opioid use disorders. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently inhibited the acquisition and maintenance of oxycodone self-administration. VK4-116 also lowered the break-point (BP) for oxycodone self-administration under a progressive-ratio schedule of reinforcement, shifted the oxycodone dose-response curve downward, and inhibited oxycodone extinction responding and reinstatement of oxycodone-seeking behavior. In addition, VK4-116 pretreatment dose-dependently enhanced the antinociceptive effects of oxycodone and reduced naloxone-precipitated conditioned place aversion in rats chronically treated with oxycodone. In contrast, VK4-116 had little effect on oral sucrose self-administration. Taken together, these findings indicate a central role for D3Rs in opioid reward and support further development of VK4-116 as an effective agent for mitigating the development of opioid addiction, reducing the severity of withdrawal and preventing relapse.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bonifazi:2017aa,

title = {Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2 Receptor (D2R) Biased Agonism.},

author = {Alessandro Bonifazi and Hideaki Yano and Michael P Ellenberger and Ludovic Muller and Vivek Kumar and Mu-Fa Zou and Ning Sheng Cai and Adrian M Guerrero and Amina S Woods and Lei Shi and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28300398},

doi = {10.1021/acs.jmedchem.6b01875},

issn = {1520-4804 (Electronic); 0022-2623 (Linking)},

year  = {2017},

date = {2017-04-17},

journal = {J Med Chem},

volume = {60},

number = {7},

pages = {2890--2907},

address = {Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.},

abstract = {The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or beta-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward beta-arrestin recruitment. Compound 19 was identified as a new lead for its selective D2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure-activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus beta-arrestin recruitment in D2R-BRET functional assays.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Kumar:2017aa,

title = {Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D3 Receptor (D3R).},

author = {Vivek Kumar and Amy E Moritz and Thomas M Keck and Alessandro Bonifazi and Michael P Ellenberger and Christopher D Sibley and Benjamin R Free and Lei Shi and Robert J Lane and David R Sibley and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28186762},

doi = {10.1021/acs.jmedchem.6b01688},

issn = {1520-4804 (Electronic); 0022-2623 (Linking)},

year  = {2017},

date = {2017-02-10},

journal = {J Med Chem},

volume = {60},

number = {4},

pages = {1478--1494},

address = {Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.},

abstract = {The development of bitopic ligands directed toward D2-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D3 receptor (D3R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing. Herein we synthesized a series of molecules in which the primary and secondary pharmacophores were derived from the D3R-selective antagonists SB269,652 (1) and SB277011A (2) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation. Incorporating a trans-cyclopropylmethyl linker between pharmacophores and manipulating linker length resulted in the identification of two bivalent noncompetitive D3R-selective antagonists, 18a and 25a, which further delineates SAR associated with allosterism at D3R and provides leads toward novel drug development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zhu:2016aa,

title = {Nanopharmacological Force Sensing to Reveal Allosteric Coupling in Transporter Binding Sites.},

author = {Rong Zhu and Doris Sinwel and Peter S Hasenhuetl and Kusumika Saha and Vivek Kumar and Peng Zhang and Christian Rankl and Marion Holy and Sonja Sucic and Oliver Kudlacek and Andreas Karner and Walter Sandtner and Thomas Stockner and Hermann J Gruber and Michael Freissmuth and Amy Hauck Newman and Harald H Sitte and Peter Hinterdorfer},

url = {https://www.ncbi.nlm.nih.gov/pubmed/26695726},

doi = {10.1002/anie.201508755},

issn = {1521-3773 (Electronic); 1433-7851 (Linking)},

year  = {2017},

date = {2017-01-26},

journal = {Angew Chem Int Ed Engl},

volume = {55},

number = {5},

pages = {1719--1722},

address = {Institute for Biophysics, Johannes Kepler University Linz, Gruberstrasse 40, 4020, Linz, Austria.},

abstract = {Controversy regarding the number and function of ligand binding sites in neurotransmitter/sodium symporters arose from conflicting data in crystal structures and molecular pharmacology. Here, we have designed novel tools for atomic force microscopy that directly measure the interaction forces between the serotonin transporter (SERT) and the S- and R-enantiomers of citalopram on the single molecule level. This approach is based on force spectroscopy, which allows for the extraction of dynamic information under physiological conditions thus inaccessible via X-ray crystallography. Two distinct populations of characteristic binding strengths of citalopram to SERT were revealed in Na(+)-containing buffer. In contrast, in Li(+) -containing buffer, SERT showed only low force interactions. Conversely, the vestibular mutant SERT-G402H merely displayed the high force population. These observations provide physical evidence for the existence of two binding sites in SERT when accessed in a physiological context. Competition experiments revealed that these two sites are allosterically coupled and exert reciprocal modulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Cao2016,

title = {Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors.},

author = {Jianjing Cao and Rachel D Slack and Oluyomi M Bakare and Caitlin Burzynski and Rana Rais and Barbara S Slusher and Theresa Kopajtic and Alessandro Bonifazi and Michael P Ellenberger and Hideaki Yano and Yi He and Guo-Hua Bi and Zheng-Xiong Xi and Claus J Loland and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27933960},

doi = {10.1021/acs.jmedchem.6b01373},

issn = {1520-4804 (Electronic); 0022-2623 (Linking)},

year  = {2016},

date = {2016-12-08},

journal = {J Med Chem},

volume = {59},

number = {23},

pages = {10676--10691},

address = {Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.},

abstract = {The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as 11b, which demonstrated high DAT affinity (Ki = 2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that 11b may be a potential lead for development as a psychostimulant abuse medication.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Kumar2016,

title = {Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment.},

author = {Vivek Kumar and Alessandro Bonifazi and Michael P Ellenberger and Thomas M Keck and Elie Pommier and Rana Rais and Barbara S Slusher and Eliot Gardner and Zhi-Bing You and Zheng-Xiong Xi and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27508895},

doi = {10.1021/acs.jmedchem.6b00860},

issn = {1520-4804 (Electronic); 0022-2623 (Linking)},

year  = {2016},

date = {2016-08-25},

journal = {J Med Chem},

volume = {59},

number = {16},

pages = {7634--7650},

address = {Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.},

abstract = {The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R Ki = 6.84 nM, 1700-fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zou2016,

title = {Novel Analogues of (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Sumanirole) Provide Clues to Dopamine D2/D3 Receptor Agonist Selectivity.},

author = {Mu-Fa Zou and Thomas M Keck and Vivek Kumar and Prashant Donthamsetti and Mayako Michino and Caitlin Burzynski and Catherine Schweppe and Alessandro Bonifazi and Benjamin R Free and David R Sibley and Aaron Janowsky and Lei Shi and Jonathan A Javitch and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27035329},

doi = {10.1021/acs.jmedchem.5b01612},

issn = {1520-4804 (Electronic); 0022-2623 (Linking)},

year  = {2016},

date = {2016-04-14},

journal = {J Med Chem},

volume = {59},

number = {7},

pages = {2973--2988},

address = {Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons , New York, New York 10027, United States.},

abstract = {Novel 1-, 5-, and 8-substituted analogues of sumanirole (1), a dopamine D2/D3 receptor (D2R/D3R) agonist, were synthesized. Binding affinities at both D2R and D3R were higher when determined in competition with the agonist radioligand [(3)H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [(3)H]N-methylspiperone. Although 1 was confirmed as a D2R-preferential agonist, its selectivity in binding and functional studies was lower than previously reported. All analogues were determined to be D2R/D3R agonists in both GoBRET and mitogenesis functional assays. Loss of efficacy was detected for the N-1-substituted analogues at D3R. In contrast, the N-5-alkyl-substituted analogues, and notably the n-butyl-arylamides (22b and 22c), all showed improved affinity at D2R over 1 with neither a loss of efficacy nor an increase in selectivity. Computational modeling provided a structural basis for the D2R selectivity of 1, illustrating how subtle differences in the highly homologous orthosteric binding site (OBS) differentially affect D2R/D3R affinity and functional efficacy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Keck2015,

title = {Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis.},

author = {Thomas M Keck and William S John and Paul W Czoty and Michael A Nader and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/25826710},

doi = {10.1021/jm501512b},

issn = {1520-4804 (Electronic); 0022-2623 (Linking)},

year  = {2015},

date = {2015-07-23},

journal = {J Med Chem},

volume = {58},

number = {14},

pages = {5361--5380},

address = {daggerMedicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.},

abstract = {The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagonists and partial agonists have shown especially promising results in rodent models of relapse-like behavior, including stress-, drug-, and cue-induced reinstatement of drug seeking. However, to date, translation to human studies has been limited. Herein, we present an overview and illustrate some of the pitfalls and challenges of developing novel D3R-selective compounds toward clinical utility, especially for treatment of cocaine abuse. Future research and development of D3R-selective antagonists and partial agonists for substance abuse remains critically important but will also require further evaluation and development of translational animal models to determine the best time in the addiction cycle to target D3Rs for optimal therapeutic efficacy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Loland2012,

title = {R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse.},

author = {Claus J Loland and Maddalena Mereu and Oluyomi M Okunola and Jianjing Cao and Thomas E Prisinzano and Sonia Mazier and Theresa Kopajtic and Lei Shi and Jonathan L Katz and Gianluigi Tanda and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/22537794},

doi = {10.1016/j.biopsych.2012.03.022},

issn = {1873-2402 (Electronic); 0006-3223 (Linking)},

year  = {2012},

date = {2012-09-01},

journal = {Biol Psychiatry},

volume = {72},

number = {5},

pages = {405--413},

address = {Molecular Neuropharmacology Laboratory, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.},

abstract = {BACKGROUND: (+/-)-Modafinil has piqued interest as a treatment for attention-deficit/hyperactivity disorder and stimulant dependence. The R-enantiomer of modafinil might have unique pharmacological properties that should be further investigated. METHODS: (+/-)-Modafinil and its R-(-)- and S-(+)-enantiomers were synthesized and tested for inhibition of [(3)H] dopamine (DA) uptake and [(3)H]WIN 35428 binding in human dopamine transporter (DAT) wild-type and mutants with altered conformational equilibria. Data were compared with cocaine and the atypical DA uptake inhibitor, JHW 007. R- and S-modafinil were also evaluated in microdialysis studies in the mouse nucleus accumbens shell and in a cocaine discrimination procedure. RESULTS: (+/-)-, R-, and S-modafinil bind to the DAT and inhibit DA uptake less potently than cocaine, with R-modafinil having approximately threefold higher affinity than its S-enantiomer. Molecular docking studies revealed subtle differences in binding modes for the enantiomers. R-modafinil was significantly less potent in the DAT Y156F mutant compared with wild-type DAT, whereas S-modafinil was affected less. Studies with the Y335A DAT mutant showed that the R- and S-enantiomers tolerated the inward-facing conformation better than cocaine, which was further supported by [2-(trimethylammonium)ethyl]-methanethiosulfonate reactivity on the DAT E2C I159C. Microdialysis studies demonstrated that both R- and S-modafinil produced increases in extracellular DA concentrations in the nucleus accumbens shell less efficaciously than cocaine and with a longer duration of action. Both enantiomers fully substituted in mice trained to discriminate cocaine from saline. CONCLUSIONS: R-modafinil displays an in vitro profile different from cocaine. Future trials with R-modafinil as a substitute therapy with the potential benefit of cognitive enhancement for psychostimulant addiction are warranted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Newman2012,

title = {Molecular determinants of selectivity and efficacy at the dopamine D3 receptor.},

author = {Amy Hauck Newman and Thijs Beuming and Ashwini K Banala and Prashant Donthamsetti and Katherine Pongetti and Alex LaBounty and Benjamin Levy and Jianjing Cao and Mayako Michino and Robert R Luedtke and Jonathan A Javitch and Lei Shi},

url = {https://www.ncbi.nlm.nih.gov/pubmed/22632094},

doi = {10.1021/jm300482h},

issn = {1520-4804 (Electronic); 0022-2623 (Linking)},

year  = {2012},

date = {2012-08-09},

journal = {J Med Chem},

volume = {55},

number = {15},

pages = {6689--6699},

address = {Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland, United States. anewman@intra.nida.nih.gov},

abstract = {The dopamine D3 receptor (D3R) has been implicated in substance abuse and other neuropsychiatric disorders. The high sequence homology between the D3R and D2R, especially within the orthosteric binding site (OBS) that binds dopamine, has made the development of D3R-selective compounds challenging. Here, we deconstruct into pharmacophoric elements a series of D3R-selective substituted-4-phenylpiperazine compounds and use computational simulations and binding and activation studies to dissect the structural bases for D3R selectivity and efficacy. We find that selectivity arises from divergent interactions within a second binding pocket (SBP) separate from the OBS, whereas efficacy depends on the binding mode in the OBS. Our findings reveal structural features of the receptor that are critical to selectivity and efficacy that can be used to design highly D3R-selective ligands with targeted efficacies. These findings are generalizable to other GPCRs in which the SBP can be targeted by bitopic or allosteric ligands.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Chien2010,

title = {Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist.},

author = {Ellen Y T Chien and Wei Liu and Qiang Zhao and Vsevolod Katritch and Gye Won Han and Michael A Hanson and Lei Shi and Amy Hauck Newman and Jonathan A Javitch and Vadim Cherezov and Raymond C Stevens},

url = {https://www.ncbi.nlm.nih.gov/pubmed/21097933},

doi = {10.1126/science.1197410},

issn = {1095-9203 (Electronic); 0036-8075 (Linking)},

year  = {2010},

date = {2010-11-19},

journal = {Science},

volume = {330},

number = {6007},

pages = {1091--1095},

address = {Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.},

abstract = {Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}