Position
Acting Scientific Director,
NIDA IRP
Chief,
Molecular Targets and Medications Discovery Branch
Chief,
Medicinal Chemistry Section
Director,
Medication Development Program
Contact
Triad Technology Center333 Cassell Drive
Room 3444
Baltimore, MD 21224
Phone: 443-740-2887
Fax: 443-740-2111
Email: anewman@intra.nida.nih.gov
Education
Post-doctoral Training - Laboratory of Medicinal Chemistry, NIDDK, NIH (advisor: Dr. Kenner C. Rice)
Ph. D. - Medicinal Chemistry, Medical College of Virginia, Virginia Commonwealth University (thesis advisor: Dr. Richard Glennon)
B.S. - Chemistry, Mary Washington College
Research Interests
Our research effort is focused on the design and synthesis of novel ligands to study the function of selected G-protein coupled receptors and monoamine transporters in the central nervous system. Highly selective compounds are designed and synthesized for characterization of these molecular targets and to develop structure-activity relationships. In addition, specific tools such as fluorescent and radiolabeled ligands are synthesized for receptor or transporter structure-function studies. My research program is currently studying the dopamine and serotonin transport systems and the dopamine D2 receptor family (D2/D3) through the design, synthesis and pharmacological evaluation of novel ligands. The combination of state of the art synthetic organic chemistry techniques with molecular modeling and interpretation of pharmacological data has resulted in the discovery of important molecular probes for studying these neurochemical targets. It is envisioned that, ultimately, this multidisciplinary approach will provide new leads toward the development of potential pharmacotherapeutic agents for the treatment of addiction.
Publications
Selected Publications
2017 |
Bonifazi, Alessandro; Yano, Hideaki; Ellenberger, Michael P; Muller, Ludovic; Kumar, Vivek; Zou, Mu-Fa; Cai, Ning Sheng; Guerrero, Adrian M; Woods, Amina S; Shi, Lei; Newman, Amy Hauck Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2 Receptor (D2R) Biased Agonism. Journal Article J Med Chem, 60 (7), pp. 2890–2907, 2017, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking). @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} } 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. |
Kumar, Vivek; Moritz, Amy E; Keck, Thomas M; Bonifazi, Alessandro; Ellenberger, Michael P; Sibley, Christopher D; Free, Benjamin R; Shi, Lei; Lane, Robert J; Sibley, David R; Newman, Amy Hauck J Med Chem, 60 (4), pp. 1478–1494, 2017, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking). @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} } 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. |
Zhu, Rong; Sinwel, Doris; Hasenhuetl, Peter S; Saha, Kusumika; Kumar, Vivek; Zhang, Peng; Rankl, Christian; Holy, Marion; Sucic, Sonja; Kudlacek, Oliver; Karner, Andreas; Sandtner, Walter; Stockner, Thomas; Gruber, Hermann J; Freissmuth, Michael; Newman, Amy Hauck; Sitte, Harald H; Hinterdorfer, Peter Nanopharmacological Force Sensing to Reveal Allosteric Coupling in Transporter Binding Sites. Journal Article Angew Chem Int Ed Engl, 55 (5), pp. 1719–1722, 2017, ISSN: 1521-3773 (Electronic); 1433-7851 (Linking). @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} } 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. |
2016 |
Cao, Jianjing; Slack, Rachel D; Bakare, Oluyomi M; Burzynski, Caitlin; Rais, Rana; Slusher, Barbara S; Kopajtic, Theresa; Bonifazi, Alessandro; Ellenberger, Michael P; Yano, Hideaki; He, Yi; Bi, Guo-Hua; Xi, Zheng-Xiong; Loland, Claus J; Newman, Amy Hauck Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors. Journal Article J Med Chem, 59 (23), pp. 10676–10691, 2016, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking). @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} } 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. |
Kumar, Vivek; Bonifazi, Alessandro; Ellenberger, Michael P; Keck, Thomas M; Pommier, Elie; Rais, Rana; Slusher, Barbara S; Gardner, Eliot; You, Zhi-Bing; Xi, Zheng-Xiong; Newman, Amy Hauck J Med Chem, 59 (16), pp. 7634–7650, 2016, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking). @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} } 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. |
Zou, Mu-Fa; Keck, Thomas M; Kumar, Vivek; Donthamsetti, Prashant; Michino, Mayako; Burzynski, Caitlin; Schweppe, Catherine; Bonifazi, Alessandro; Free, Benjamin R; Sibley, David R; Janowsky, Aaron; Shi, Lei; Javitch, Jonathan A; Newman, Amy Hauck J Med Chem, 59 (7), pp. 2973–2988, 2016, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking). @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} } 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. |
2015 |
Keck, Thomas M; John, William S; Czoty, Paul W; Nader, Michael A; Newman, Amy Hauck Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis. Journal Article J Med Chem, 58 (14), pp. 5361–5380, 2015, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking). @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} } 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. |
2012 |
Loland, Claus J; Mereu, Maddalena; Okunola, Oluyomi M; Cao, Jianjing; Prisinzano, Thomas E; Mazier, Sonia; Kopajtic, Theresa; Shi, Lei; Katz, Jonathan L; Tanda, Gianluigi; Newman, Amy Hauck R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Journal Article Biol Psychiatry, 72 (5), pp. 405–413, 2012, ISSN: 1873-2402 (Electronic); 0006-3223 (Linking). @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} } 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. |
Newman, Amy Hauck; Beuming, Thijs; Banala, Ashwini K; Donthamsetti, Prashant; Pongetti, Katherine; LaBounty, Alex; Levy, Benjamin; Cao, Jianjing; Michino, Mayako; Luedtke, Robert R; Javitch, Jonathan A; Shi, Lei Molecular determinants of selectivity and efficacy at the dopamine D3 receptor. Journal Article J Med Chem, 55 (15), pp. 6689–6699, 2012, ISSN: 1520-4804 (Electronic); 0022-2623 (Linking). @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} } 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. |
2010 |
Chien, Ellen Y T; Liu, Wei; Zhao, Qiang; Katritch, Vsevolod; Han, Gye Won; Hanson, Michael A; Shi, Lei; Newman, Amy Hauck; Javitch, Jonathan A; Cherezov, Vadim; Stevens, Raymond C Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Journal Article Science, 330 (6007), pp. 1091–1095, 2010, ISSN: 1095-9203 (Electronic); 0036-8075 (Linking). @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} } 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. |
