National Institute on Drug Abuse Intramural Research Program

Position

Former Post-doctoral IRTA Fellow, Medicinal Chemistry Section

Contact

Triad Technology Center
333 Cassell Drive
Baltimore, MD 21224

Education

Ph.D. – Chemistry – Johns Hopkins University (Advisor: Prof. John Toscano)

M.A. – Chemistry – Johns Hopkins University (Advisor: Prof. John Tovar)

B.S. – Chemistry – Randolph-Macon College (Advisor: Prof. John Thoburn)

Research Interests

Daryl Guthrie received his B.S. in chemistry in 2005 from Randolph-Macon College, where under Prof. John Thoburn’s mentorship, he developed squaraine dyes for applications in molecular chiroptical dipole switches and optical data storage. Daryl then obtained his M.A. (2008) and Ph.D. (2014) in chemistry from Johns Hopkins University. Upon completion of his master’s degree studying photochromic conductive materials in Prof. J.D. Tovar’s lab, Daryl joined Prof. John Toscano’s lab. There, he designed HNO prodrug therapeutics for heart failure treatments. After receiving his Ph.D., Daryl continued as a postdoctoral fellow in the Toscano lab, on a project supported by Cardioxyl Pharmaceuticals. In 2015, Daryl became an IRTA Postdoctoral Fellow in Dr. Amy H. Newman’s lab at the Medicinal Chemistry Section of the Molecular Targets and Medications Discovery Branch. Here, he will further pursue his passion for organic chemistry and drug design, by developing novel fluorescent ligands for structure function studies of the dopamine transporter (DAT), mediator of dopamine reuptake from the synaptic cleft and principle target for widely abused psychostimulants, such as cocaine and amphetamine. The fluorescent probes will be applied to study the effects of psychostimulants (and potential medications thereof) on the cellular distribution and trafficking of natively expressed DAT.

Publications

PubMed

Selected Publications

2017

Zou, Mu-Fa; Cao, Jianjing; Abramyan, Ara M; Kopajtic, Theresa; Zanettini, Claudio; Guthrie, Daryl A; Rais, Rana; Slusher, Barbara S; Shi, Lei; Loland, Claus J; Newman, Amy Hauck

Structure-Activity Relationship Studies on a Series of 3alpha-[Bis(4-fluorophenyl)methoxy]tropanes and 3alpha-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders. Journal Article

In: J Med Chem, vol. 60, no. 24, pp. 10172–10187, 2017, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking).

Abstract | Links

@article{Zou:2017aa,

title = {Structure-Activity Relationship Studies on a Series of 3alpha-[Bis(4-fluorophenyl)methoxy]tropanes and 3alpha-[Bis(4-fluorophenyl)methylamino]tropanes As Novel Atypical Dopamine Transporter (DAT) Inhibitors for the Treatment of Cocaine Use Disorders.},

author = {Mu-Fa Zou and Jianjing Cao and Ara M Abramyan and Theresa Kopajtic and Claudio Zanettini and Daryl A Guthrie and Rana Rais and Barbara S Slusher and Lei Shi and Claus J Loland and Amy Hauck Newman},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29227643},

doi = {10.1021/acs.jmedchem.7b01454},

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

year  = {2017},

date = {2017-12-28},

journal = {J Med Chem},

volume = {60},

number = {24},

pages = {10172--10187},

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 medications to treat cocaine use disorders has thus far defied success, leaving this patient population without pharmacotherapeutic options. As the dopamine transporter (DAT) plays a prominent role in the reinforcing effects of cocaine that can lead to addiction, atypical DAT inhibitors have been developed that prevent cocaine from binding to DAT, but they themselves are not cocaine-like. Herein, a series of novel DAT inhibitors were synthesized, and based on its pharmacological profile, the lead compound 10a was evaluated in phase I metabolic stability studies in mouse liver microsomes and compared to cocaine in locomotor activity and drug discrimination paradigms in mice. A molecular dynamic simulation study supported the hypothesis that atypical DAT inhibitors have similar binding poses at DAT in a conformation that differs from that of cocaine. Such differences may ultimately contribute to their unique behavioral profiles and potential for development as cocaine use disorder therapeutics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

Ma, Shiqi; Cheng, Mary H; Guthrie, Daryl A; Newman, Amy Hauck; Bahar, Ivet; Sorkin, Alexander

Targeting of dopamine transporter to filopodia requires an outward-facing conformation of the transporter. Journal Article

In: Sci Rep, vol. 7, no. 1, pp. 5399, 2017, ISSN: 2045-2322 (Electronic); 2045-2322 (Linking).

Abstract | Links

@article{Ma:2017aa,

title = {Targeting of dopamine transporter to filopodia requires an outward-facing conformation of the transporter.},

author = {Shiqi Ma and Mary H Cheng and Daryl A Guthrie and Amy Hauck Newman and Ivet Bahar and Alexander Sorkin},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28710426},

doi = {10.1038/s41598-017-05637-x},

issn = {2045-2322 (Electronic); 2045-2322 (Linking)},

year  = {2017},

date = {2017-07-14},

urldate = {2017-07-14},

journal = {Sci Rep},

volume = {7},

number = {1},

pages = {5399},

address = {Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.},

abstract = {Dopamine transporter (DAT) has been shown to accumulate in filopodia in neurons and non-neuronal cells. To examine the mechanisms of DAT filopodial targeting, we used quantitative live-cell fluorescence microscopy, and compared the effects of the DAT inhibitor cocaine and its fluorescent analog JHC1-64 on the plasma membrane distribution of wild-type DAT and two non-functional DAT mutants, R60A and W63A, that do not accumulate in filopodia. W63A did not bind JHC1-64, whereas R60A did, although less efficiently compared to the wild-type DAT. Molecular dynamics simulations predicted that R60A preferentially assumes an outward-facing (OF) conformation through compensatory intracellular salt bridge formation, which in turn favors binding of cocaine. Imaging analysis showed that JHC1-64-bound R60A mutant predominantly localized in filopodia, whereas free R60A molecules were evenly distributed within the plasma membrane. Cocaine binding significantly increased the density of R60A, but not that of W63A, in filopodia. Further, zinc binding, known to stabilize the OF state, also increased R60A concentration in filopodia. Finally, amphetamine, that is thought to disrupt DAT OF conformation, reduced the concentration of wild-type DAT in filopodia. Altogether, these data indicate that OF conformation is required for the efficient targeting of DAT to, and accumulation in, filopodia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}