Bryan L Roth

University of North Carolina at Chapel Hill, North Carolina, United States

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Publications (388)2370.41 Total impact

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    ABSTRACT: The hypothesis that functionally selective GPCR agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their utility is limited by a propensity to induce sedation, motor incoordination, hallucinations and dysphoria-like states. Several labs have produced a body of work implying that G-protein biased KOR agonists might be analgesic with fewer side-effects. Although this has been an intriguing hypothesis, suitably KOR selective and G-protein biased agonists have not been available to test this idea. Here we provide data using a G-protein biased agonist RB-64 which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas β-arrestin 2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB 64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence with a highly selective and G-protein biased tool compound that many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein biased KOR agonists.
    Journal of Pharmacology and Experimental Therapeutics 10/2014; · 3.89 Impact Factor
  • Daniel J Urban, Bryan L Roth
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    ABSTRACT: In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein-coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 55 is January 06, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    Annual review of pharmacology and toxicology. 09/2014;
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    ABSTRACT: The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand-receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure-activity relationships, and previous salvinorin A-KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR.
    Planta Medica 08/2014; · 2.35 Impact Factor
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    ABSTRACT: Previous work from our labs has indicated that a tropane analog of haloperidol with potent D2 binding but designed to avoid the formation of MPP(+)-like metabolites, such as 4-(4-chlorophenyl)-1-(4-(4-fluorophenyl)-4-oxobutyl)pyridin-1-ium (BCPP(+)) still produced catalepsy, suggesting a strong role for the D2 receptor in the production of catalepsy in rats, and hence EPS in humans. This study tested the hypothesis that further modifications of the tropane analog to produce compounds with less potent binding to the D2 receptor than haloperidol, would produce less catalepsy. These tests have now revealed that while haloperidol produced maximum catalepsy, these compounds produced moderate to low levels of catalepsy. Compound 9, with the least binding affinity to the D2R, produced the least catalepsy and highest Minimum Adverse Effective Dose (MAED) of the analogs tested regardless of their affinities at other receptors including the 5-HT1AR. These observations support the hypothesis that moderation of the D2 binding of the tropane analogs could reduce catalepsy potential in rats and consequently EPS in man.
    Bioorganic & medicinal chemistry letters. 07/2014;
  • Hu Zhu, Bryan L Roth
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    ABSTRACT: In this issue of Neuron, Stachniak et al. (2014) determine that the chemogenetic silencer hM4Di-DREADD suppresses presynaptic glutamate release, and by generating an axon-targeted hM4Di variant they demonstrate that it can be used to locally silence synaptic transmission in neural circuits.
    Neuron. 05/2014; 82(4):723-5.
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    ABSTRACT: GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorders. The signal transduction pathway and receptor functions of GPR88, however, are still largely unknown due to the lack of endogenous and synthetic ligands. In this paper, we report the synthesis of a GPR88 agonist 2-PCCA and its pure diastereomers, which were functionally characterized in both transiently and stably expressing GPR88 HEK293 cells. 2-PCCA inhibited isoproterenol-stimulated cAMP accumulation in a concentration-dependent manner in cells expressing GPR88 but not in the control cells, suggesting that the observed cAMP inhibition is mediated through GPR88 and that GPR88 is coupled to Gαi. 2-PCCA did not induce calcium mobilization in GPR88 cells, indicating no Gαq-mediated response. A structure-activity relationship (SAR) study of 2-PCCA was also conducted to explore the key structural features for GPR88 agonist activity.
    ACS Chemical Neuroscience 05/2014; · 3.87 Impact Factor
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    ABSTRACT: Despite their functional and structural diversity, G-protein-coupled receptors (GPCRs) share a common mechanism of signal transduction via conformational changes in the seven-transmembrane (7TM) helical domain. New major insights into this mechanism come from the recent crystallographic discoveries of a partially hydrated sodium ion that is specifically bound in the middle of the 7TM bundle of multiple class A GPCRs. This review discusses the remarkable structural conservation and distinct features of the Na(+) pocket in this most populous GPCR class, as well as the conformational collapse of the pocket on receptor activation. New insights help to explain allosteric effects of sodium on GPCR agonist binding and activation, and highlight its role as a key co-factor in class A GPCR function.
    Trends in Biochemical Sciences 04/2014; · 13.08 Impact Factor
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    ABSTRACT: The dopamine D4 receptor has been shown to play key roles in certain CNS pathologies including addiction to cigarette smoking. Thus, selective D4 ligands may be useful in treating some of these conditions. Previous studies in our laboratory have indicated that the piperazine analog of haloperidol exhibits selective and increased affinity to the DAD4 receptor subtype, in comparison to its piperidine analog. This led to further exploration of the piperazine moiety to identify new agents that are selective at the D4 receptor. Compound 27 (KiD4=0.84nM) was the most potent of the compounds tested. However, it only had moderate selectivity for the D4 receptor. Compound 28 (KiD4=3.9nM) while not as potent, was more discriminatory for the D4 receptor subtype. In fact, compound 28 has little or no binding affinity to any of the other four DA receptor subtypes. In addition, of the 23 CNS receptors evaluated, only two, 5HT1AR and 5HT2BR, have binding affinity constants better than 100nM (Ki <100nM). Compound 28 is a potentially useful D4-selective ligand for probing disease treatments involving the D4 receptor, such as assisting smoking cessation, reversing cognitive deficits in schizophrenia and treating erectile dysfunction. Thus, further optimization, functional characterization and evaluation in animal models may be warranted.
    Bioorganic & medicinal chemistry 04/2014; · 2.82 Impact Factor
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    ABSTRACT: The G protein-coupled receptor (GPCR) family is among the most druggable families in the human proteome. GPCRs are involved in most physiological processes, and our ability to modulate their activity is a hallmark of modern pharmacology. The means by which the activity of GPCRs can be modulated have been expanded by emerging data and concepts in pharmacology, which has created new strategies for their control. These new approaches will lead to the generation of more potent, selective, and efficient pharmaceutics, while reducing inappropriate actions and adverse effects. Herein, we review and comment on some recent advances in chemical and genetic approaches to the profiling of GPCR function, as well as the validation of orphan GPCRs as potential therapeutic targets using engineered receptors.
    Current opinion in cell biology 04/2014; 27C:51-55. · 14.15 Impact Factor
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    ABSTRACT: Synaptic consolidation is a process thought to consolidate memory in the brain. Although lesion studies have mainly implicated the hippocampus in this process, it is unknown which cell type(s) or regions of the hippocampus might be essential for synaptic consolidation. To selectively and reversibly suppress hippocampal neuronal activity during this process, we developed a new Gi-DREADD (hM4Di) transgenic mouse for in vivo manipulation of neuronal activity in freely moving animals. We found that CA1 pyramidal neurons could be dose-dependently inactivated by clozapine-n-oxide (CNO). Inactivation of hippocampal neurons within 6 h immediately after conditioned fear training successfully impaired the consolidation of contextual memory, without disturbing cued memory. To anatomically define the brain subregion critical for the behavioral effects, hM4Di viral vectors were transduced and selectively expressed in the glutamatergic neurons in either the dorsal or ventral hippocampus. Significantly, we found that selective inactivation of ventral but not dorsal glutamatergic hippocampal neurons suppressed the synaptic consolidation of contextualmemory.Neuropsychopharmacology accepted article preview online, 14 February 2014; doi:10.1038/npp.2014.35.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2014; · 8.68 Impact Factor
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    ABSTRACT: Opioids represent widely prescribed and abused medications, although their signal transduction mechanisms are not well understood. Here we present the 1.8 Å high-resolution crystal structure of the human δ-opioid receptor (δ-OR), revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive δ-OR sodium ion site architecture is centrally located in a polar interaction network in the seven-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies reveal that changing the allosteric sodium site residue Asn 131 to an alanine or a valine augments constitutive β-arrestin-mediated signalling. Asp95Ala, Asn310Ala and Asn314Ala mutations transform classical δ-opioid antagonists such as naltrindole into potent β-arrestin-biased agonists. The data establish the molecular basis for allosteric sodium ion control in opioid signalling, revealing that sodium-coordinating residues act as 'efficacy switches' at a prototypic G-protein-coupled receptor.
    Nature 01/2014; · 38.60 Impact Factor
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    ABSTRACT: The 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification Quantitative Structure-Activity Relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external five-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the WOMBAT database. These validated models were then used to mine three major types of chemical screening libraries, i.e., drug-like libraries, GPCR targeted libraries, and diversity libraries, to identify novel computational hits. The five best hits from each class of libraries were chosen for further experimental testing in radioligand binding assays, and nine of the 15 hits were confirmed to be active experimentally with binding affinity better than 10 µM. The most active compound, Lysergol, from the diversity library showed very high binding affinity (Ki) of 2.3 nM against 5-HT1A receptor. The novel 5-HT1A actives identified with the QSAR-based virtual screening approach could be potentially developed as novel anxiolytics or potential anti-schizophrenic drugs.
    Journal of Chemical Information and Modeling 01/2014; · 4.30 Impact Factor
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    ABSTRACT: The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumours; however, mutations at SMO have been found to abolish their antitumour effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6-2.8 Å resolution. The long and narrow cavity in the transmembrane domain of SMO harbours multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D473(6.54f) elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules.
    Nature Communications 01/2014; 5:4355. · 10.74 Impact Factor
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    ABSTRACT: We report on the development of the HTS Navigator software to analyze and visualize the results of high-throughput screening (HTS) of chemical libraries. The HTS Navigator processes output files from different plate readers' formats, computes the overall HTS matrix, automatically detects hits and has different types of baseline navigation and correction features. The software incorporates advanced cheminformatics capabilities such as chemical structure storage and visualization, fast similarity search, and chemical neighborhood analysis for retrieved hits. The software is freely available for academic laboratories. http://fourches.web.unc.edu/Contacts: fourches@email.unc.edu; alex_tropsha@unc.edu SUPPLEMENTARY INFORMATION: Supplementary figure and data on system requirements are available at Bioinformatics online.
    Bioinformatics 12/2013; · 5.47 Impact Factor
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    ABSTRACT: Background: Serotonin modulates many processes through a family of seven serotonin receptors. However, no studies have screened for interactions between general anesthetics currently in clinical use and serotonergic G-protein-coupled receptors (GPCRs). Given that both intravenous and inhalational anesthetics have been shown to target other classes of GPCRs, we hypothesized that general anesthetics might interact directly with some serotonin receptors and thus modify their function. Methods: Radioligand binding assays were performed to screen serotonin receptors for interactions with propofol and isoflurane as well as for affinity determinations. Docking calculations using the crystal structure of 5-HT2B were performed to computationally confirm the binding assay results and locate anesthetic binding sites. Results: The 5-HT2B class of receptors interacted significantly with both propofol and isoflurane in the primary screen. The affinities for isoflurane and propofol were determined to be 7.78 and .95 μM, respectively, which were at or below the clinical concentrations for both anesthetics. The estimated free energy derived from docking calculations for propofol (-6.70 kcal/mol) and isoflurane (-5.10 kcal/mol) correlated with affinities from the binding assay. The anesthetics were predicted to dock at a pharmacologically relevant binding site of 5HT2B. Conclusions: The molecular interactions between propofol and isoflurane with the 5-HT2B class of receptors were discovered and characterized. This finding implicates the serotonergic GPCRs as potential anesthetic targets.
    Journal of biomolecular structure & dynamics 12/2013; · 4.99 Impact Factor
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    ABSTRACT: Although dezocine is a partial μ-opioid receptor agonist, it is not a controlled substance. Thus, the characterization of the molecular targets of dezocine is critical for scientific and clinical implications. The goal of this study is to characterize molecular targets for dezocine and determine their implications. A binding screen for dezocine was performed on 44 available receptors and transporter proteins. Functional assays for the novel targets were performed along with computation calculations to locate the binding site. A G protein activation study was performed for the human κ opioid receptor to determine whether dezocine is a κ-antagonist. Data are presented as mean ± standard error. The affinities for dezocine were 3.7 ± 0.7 nM for the μ receptor, 527 ± 70 nM for the δ-receptor, and 31.9 ± 1.9 nM for the κ-receptor. Dezocine failed to induce G protein activation with κ-opioid receptor and concentration dependently inhibited κ-agonist (salvinorin A and nalbuphine)-induced receptor activation, indicating that dezocine is a κ-antagonist. Two novel molecular targets (norepinephrine transporter and serotonin transporter) were identified. Dezocine concentration-dependently inhibited norepinephrine and serotonin reuptake in vitro. The half maximal inhibitory concentrations (expressed as pIC50) were 5.68 ± 0.11 for norepinephrine transporter and 5.86 ± 0.17 for serotonin transporter. Dezocine occupied the binding site for known norepinephrine transporter and serotonin transporter inhibitors. The unique molecular pharmacological profile of dezocine as a partial μ-receptor agonist, a κ-receptor antagonist, and a norepinephrine and serotonin reuptake inhibitor (via norepinephrine transporter and serotonin transporter) was revealed. These discoveries reveal potentially important novel clinical implications and drug interactions of dezocine.
    Anesthesiology 11/2013; · 5.16 Impact Factor
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    ABSTRACT: Phenotypic screens can identify molecules that are at once penetrant and active on the integrated circuitry of a whole cell or organism. These advantages are offset by the need to identify the targets underlying the phenotypes. Additionally, logistical considerations limit screening for certain physiological and behavioral phenotypes to organisms such as zebrafish and C. elegans. This further raises the challenge of elucidating whether compound-target relationships found in model organisms are preserved in humans. To address these challenges we searched for compounds that affect feeding behavior in C. elegans and sought to identify their molecular mechanisms of action. Here, we applied predictive chemoinformatics to small molecules previously identified in a C. elegans phenotypic screen likely to be enriched for feeding regulatory compounds. Based on the predictions, 16 of these compounds were tested in vitro against 20 mammalian targets. Of these, nine were active, with affinities ranging from 9 nM to 10 µM. Four of these nine compounds were found to alter feeding. We then verified the in vitro findings in vivo through genetic knockdowns, the use of previously characterized compounds with high affinity for the four targets, and chemical genetic epistasis, which is the effect of combined chemical and genetic perturbations on a phenotype relative to that of each perturbation in isolation. Our findings reveal four previously unrecognized pathways that regulate feeding in C. elegans with strong parallels in mammals. Together, our study addresses three inherent challenges in phenotypic screening: the identification of the molecular targets from a phenotypic screen, the confirmation of the in vivo relevance of these targets, and the evolutionary conservation and relevance of these targets to their human orthologs.
    PLoS Biology 11/2013; 11(11):e1001712. · 12.69 Impact Factor
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    ABSTRACT: Since the invention of the first designer receptors exclusively activated by designer drugs (DREADDs), these engineered G protein-coupled receptors (GPCRs) have been widely applied in investigations of biological processes and behaviors. DREADD technology has emerged as a powerful tool with great potential for drug discovery and development. DREADDs can facilitate the identification of druggable targets and enable researchers to explore the activities of novel drugs against both known and orphan GPCRs. Here, we discuss how DREADDs can be used as novel tools for drug discovery and development.
    Drug discovery today 10/2013; · 6.63 Impact Factor
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    ABSTRACT: In previous studies we reported that addition of 7α-acylamino groups to N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to compounds that were pure opioid receptor antagonists. In contrast to these findings we report in this study that addition of a 7α-amino (5a), 7α-alkylamino (5b-e), or 7α-dialkylamino 5f-h) group to 4 leads to opioid receptor ligands with varying degrees of agonist/antagonist activity. The 7α-amino and 7α-methylamino analogues were full agonists at the μ and δ receptors and antagonists at the κ receptor. The 7α-cyclopropylmethylamino analogue 5h was a full agonist at the μ receptor with weaker agonist activity at the δ and κ receptors. Whereas the addition of a 7α-acylamino group to the pure non-selective opioid receptor antagonist N-phenylpropyl-4β-methyl-5-(3-hydroxyphenyl)morphan (4) led to κ selective pure opioid receptor antagonist, the addition of a 7α-amino, 7α-alkylamino or 7α-dialkylamino group to 4 leads to opioid ligands that are largely μ or δ agonist with mixed agonist/antagonist properties.
    Journal of Medicinal Chemistry 10/2013; · 5.61 Impact Factor
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    ABSTRACT: The crystal structures of opioid receptors provide a novel platform for inquiry into opioid receptor function. The molecular determinants for activation of the k-opioid receptor (KOR) were studied using a combination of agonist docking, functional assays and site-directed mutagenesis. Eighteen positions in the putative agonist binding site of KOR were selected and evaluated for their effects on receptor binding and activation by ligands representing four distinct chemotypes: the peptide dynorphin A (1 to 17), the arylacetamide U-69593, and the non-charged ligands salvinorin A and the octahydroisoquinolinone carboxamide 1xx. Minimally biased docking of the tested ligands into the antagonist-bound KOR structure generated distinct binding modes which were then evaluated biochemically and pharmacologically. Our analysis identified two types of mutations: those that affect receptor function primarily via ligand binding and those that primarily affect function. The shared and differential mechanisms of agonist binding and activation in KOR are further discussed. Usually, mutations affecting function more than binding were located at the periphery of the binding site and did not interact strongly with the various ligands. Analysis of the crystal structure along with the present results provide fundamental insights into the activation mechanism of the KOR, and suggest that functional residues, along with water molecules detected in the crystal structure, may be directly involved in transduction of the agonist binding event into structural changes at the conserved rotamer switches, thus leading to receptor activation.
    Journal of Biological Chemistry 10/2013; · 4.65 Impact Factor

Publication Stats

13k Citations
2,370.41 Total Impact Points

Institutions

  • 2006–2014
    • University of North Carolina at Chapel Hill
      • • Division of Chemical Biology and Medicinal Chemistry
      • • Department of Pharmacology
      • • Department of Medicine
      North Carolina, United States
    • Organix Inc.
      Woburn, Massachusetts, United States
    • Robert Wood Johnson University Hospital
      New Brunswick, New Jersey, United States
  • 2013
    • McLean Hospital
      Cambridge, Massachusetts, United States
    • Yonsei University
      • Department of Chemistry
      Sŏul, Seoul, South Korea
    • Korea Institute of Science and Technology
      • Center for Neuro-Medicine
      Seoul, Seoul, South Korea
  • 2007–2013
    • University of California, San Francisco
      • • Department of Pharmaceutical Chemistry
      • • Department of Psychiatry
      San Francisco, CA, United States
    • Université du Droit et de la Santé Lille 2
      • Laboratoire de Chimie Thérapeutiques 2
      Lille, Nord-Pas-de-Calais, France
  • 2006–2013
    • University of Mississippi
      • • School of Pharmacy
      • • National Center for Natural Products Research
      • • Department of Pharmacognosy
      University, MS, United States
  • 2012
    • University of Liège
      Luik, Walloon Region, Belgium
    • Anyang Normal University
      Chang-te, Henan Sheng, China
    • University of Oxford
      • Department of Pharmacology
      Oxford, ENG, United Kingdom
    • The Scripps Research Institute
      • Department of Cell and Molecular Biology
      La Jolla, CA, United States
  • 2008–2012
    • University of Wisconsin - Milwaukee
      • Department of Chemistry and Biochemistry
      Milwaukee, WI, United States
    • Vanderbilt University
      • Department of Pharmacology
      Nashville, Michigan, United States
  • 2006–2012
    • Florida A&M University
      • Division of Basic and Pharmaceutical Sciences
      Tallahassee, FL, United States
  • 1984–2012
    • National Institute of Mental Health (NIMH)
      Maryland, United States
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 2011
    • University of Toronto
      • Structural Genomics Consortium
      Toronto, Ontario, Canada
    • University of Pittsburgh
      • School of Nursing
      Pittsburgh, PA, United States
    • Konkuk University
      • Department of Bioscience and Technology
      Sŏul, Seoul, South Korea
  • 2006–2011
    • University of Illinois at Chicago
      • Department of Medicinal Chemistry and Pharmacognosy
      Chicago, IL, United States
  • 2010
    • University of Maryland, Baltimore
      • Department of Anatomy and Neurobiology
      Baltimore, MD, United States
    • University of Belgrade
      • Faculty of Pharmacy
      Belgrade, SE, Serbia
  • 2004–2010
    • University of Richmond
      Richmond, Virginia, United States
    • University of Washington Seattle
      • Department of Biochemistry
      Seattle, WA, United States
  • 2002–2010
    • Virginia Commonwealth University
      • Department of Medicinal Chemistry
      Richmond, VA, United States
    • University of Münster
      • Institute of Pharmacology and Toxicology
      Münster, North Rhine-Westphalia, Germany
  • 1996–2010
    • Case Western Reserve University
      • • Department of Biochemistry
      • • Department of Psychiatry (University Hospitals Case Medical Center)
      Cleveland, OH, United States
  • 1992–2010
    • Case Western Reserve University School of Medicine
      • Department of Psychiatry
      Cleveland, Ohio, United States
  • 2009
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Pharmacology and Experimental Therapeutics
      Baton Rouge, LA, United States
    • Duke University Medical Center
      • Department of Neurobiology
      Durham, NC, United States
  • 2005
    • Columbia University
      • Department of Psychiatry
      New York City, NY, United States
    • CUNY Graduate Center
      New York City, New York, United States
  • 2003
    • Georgetown University
      • Department of Neuroscience
      Washington, D. C., DC, United States
    • National Institute on Drug Abuse
      Maryland, United States
  • 2001
    • National Institutes of Health
      • Division of Intramural Research (Dental Research)
      Bethesda, MD, United States
  • 1989
    • Stanford Medicine
      • Department of Psychiatry and Behavioral Sciences
      Stanford, California, United States
    • Stanford University
      • Department of Psychiatry and Behavioral Sciences
      Stanford, CA, United States
  • 1980–1983
    • Washington University in St. Louis
      San Luis, Missouri, United States