Aloke Dutta Ph.D.

1986, Doctor of Philosophy, Organic Chemistry, Ohio     University, Athens (Minor in Biochemistry and Inorganic Chemistry)
1981, Master of Science, Organic Chemistry, Calcutta University, Calcutta (Minor in Inorganic and Physical Chemistry)

Ph.D.

EDITORIAL BOARD MEMBER:            
Editorial board membership of the journal “Current Medicinal Chemistry-Central Nervous System”.

Editorial board membership of the journal “The open bioactive compounds journal”.

MEMBER OF NIH/NIDA STUDY SECTIONS:
Currently serving in NIDA/NIH study section to review     SBIR proposals, 1999-Present.
Member of Study Section for reviewing “Cutting Edge     Basic Research Award Program” (CEBRA) NIH/NIDA
Reviewer of Research Protocol and Drug Supply program  for NIH/NIDA, 1997-Present
Reviewed R01 proposal as an ad hoc member for  Molecular, Cellular and Developmental Neurosciences (MCDN) study (NIH/CSR) section

Reviewer of Research Corporation: A foundation for advancement of science

STANDING COMMITTEE MEMBER OF NIH STUDY SECTION
Standing committee member of NIH/NIDA  “Medication Development Research Subcommittee” , 2007-2011

JOURNAL REVIEWERS:
Reviewer of Journal of Medicinal Chemistry.
Reviewer of Bioorganic and Medicinal Chemistry Letters.
Reviewer of Bioorganic and Medicinal Chemistry.
Reviewer of Medicinal Chemistry Research
Reviewer of Current Medicinal Chemistry-Central Nervous System Agents
Reviewer, Australian Journal of Chemistry
Reviewer, Drug and alcohol dependence
Reviewer, European Journal of Medicinal Chemistry
Current Topics in Medicinal Chemistry
Tetrahedron
Biochemical Pharmacology
British Journal of Pharmacology
Archiv der Pharmazie

1985    Research Associate, awarded by the Department of Chemistry, Ohio University.
1994    Recipient of NIH/NIDA FIRST Award, R29, 1994


Past Funded Proposals

1.  NIH/NIDA: First Independent Research Support and Transition Award
"Potent and Selective Probes for the Dopamine Transporter."
Duration: 9/1/94 to 9/1/99
 P.I: Aloke. K. Dutta

2. Wayne State University Faculty Research Grant #1-41824 awarded March 4, 1999. Title of proposal: Design and Synthesis of Novel Nitric Oxide Synthase Inhibitors
Duration: May 1, 1999 –April 30, 2000
P.I.: Aloke K. Dutta, Ph.D.
       
3. NIH/NIDA: "Dopamine transporter agents against cocaine dependence"
Duration: 12/1/99 to 11/30/2005
P.I.: Aloke K. Dutta

4. National Institutes of Health RO1 grant (NIH/NIDA)
Co-Investigator: Aloke K. Dutta, Ph.D.
Title of the Proposal: Affinity Labelling the Dopamine Transporter Active Site
Funding Period: 5/01/03-4/30/06

B. Michigan Universities Commercialization Initiative (MUCI) Application

5. Title: Manufacture and Score 2000 Testing of WSU CNS Compounds (Dopamine Transporter Inhibitors) for use as a wake-cognition therapies
Principal Investigator:     Aloke K. Dutta, Ph.D.
Funding period: July 2004 to August 2005

6. Title: Novel D3 receptor compounds (evaluation for application in Parkinson’s Disease)
Principal Investigator:     Aloke K. Dutta, Ph.D.
Funding period: Q3 2004 to Q1 2006

       
Current Active Grants

7. NIH/NINDS:
Title of the proposal: Novel neuroprotective treatment  for Parkinson’s Disease
Duration: 05/01/05-04/30/10
Principal Investigator: Aloke K. Dutta, Ph.D.


8. NIH/NIDA: "Dopamine transporter agents against cocaine dependence"
Duration: 09/25/2005 to 08/31/2009
P.I.: Aloke K. Dutta

9. 7 R01 DA13261-06             
Funding period: 09/01/2006 – 08/31/2011           
Co-Investigator: Aloke K. Dutta, Ph.D.
NIH/NIDA: Dopamine transporters and ions, substrates, blockers

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10. Title: TRIPLE UPTAKE INHIBITORS AS NOVEL ANTIDEPRESSANT

NIH/NIMH

Funding Period: 07/01/2009 to 06/30/2014

Total Cost: $1,906,683

Principal Investigator: Aloke K. Dutta, Ph.D.

11. Title: Triple Monoamine Reuptake Inhibitor as New Generation Antidepressants

Principal Investigator: Aloke K. Dutta, Ph.D.

Funding period: Q4 2008 to Q4 2009

Total Cost: $118,000

BOOK CHAPTER

1. Kharkar, P; Reith, M. E. A; Dutta A. K. Piperidine-based dopamine transporter uptake inhibitors: Dopamine Transporters: Chemistry, Biology and Pharmacology: Edited by Mark Trudell and Sari Izenwasser, Wiley Publisher, 2007.

Peer Reviewed Publications (2000-current)

1. Dutta A. K,  Fei X-S, Vaughn R A, Gaffaney J D, Wang N, Lever J R, Reith M. Design, Synthesis, and Characterization of a Novel, 4-[2-    (Diphenylmethoxy)ethyl]-1-Benzyl Piperidine-Based, Dopamine Transporter Photoaffinity Label. Life Sciences, 68/16, 1839-1849,     2001.

2. Dutta A K, Neisewander J, Fuchs R, Reith M. Synthesis and Characterization of Novel Derivatives of 2-Aminotetralins: Development of Highly Selective Derivatives for the D3 receptor. Med. Chem.  Res. 10:4, 208-229, 2000.

3. Dutta A. K, Fei X-S,  Beardsley P. M, Reith M. E. A. Novel N- and O-Substituted 4-[2-(Diphenylmethoxy)-ethyl]-1-[(phenyl)methyl]piperidine analogs. Drug and Alcohol Dependence, Volume 60, Suppl 1, S55, 2000.

4. Vaughan R A, Gaffaney J D, Lever J R, Reith M, Dutta A K. Dual Incorporation of Photoaffinity Ligands on Dopamine Transporters  Implicates Proximity of Labeled Domains. Molecular Pharmacology, 59,     1157-1164, 2001.

5. Dutta A. K, Fei X-S, Beardsley P, Newman J, Reith M. E. A. Structure-Activity Relationship Studies of 4-[2 (Diphenylmethoxy)ethyl]-1-benzylpiperidine Derivatives and their N-analogs: Evaluation of Behavioral Activity of O-and N-Analogs and their Binding to Monoamine transporters. J. Med. Chem. 44, 3, 937-948, 2001.

6. Dutta A K, Reith M. E. A, Madras B. K. Synthesis and Preliminary Characterization of  a High Affinity Novel Radioligand For The Dopamine  Transporter”. SYNAPSE, 39, 175-181, 2001.

7. Dutta A K, Reith M. Synthesis and biological characterization of novel dopamine transporter specific molecules.Publication from 52nd     Southeast and 56th Southwest combined regional meeting of the American Chemical Society, Programm Abstracts, 174, 2000.

8. Dutta A K, Davis M C,  Reith M. E. A. Reith. Rational Design and synthesis of novel conformationally constrained 2,5-disubstituted cis- and tras-piperidine derivatives exhibiting differential activity for the dopamine transporter. Bioorg. Med. Lett. 11, 2337-2340, 2001.

9. Dutta A K, Davis M, Fei X-S, Beardsley P. M, Cook C D, Reith M. E. A. Expansion of Structure-Activity Studies in piperidine analogues of 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935) compounds by altering substitutions in the N-benzyl moiety and behavioral pharmacology of selected molecules. J. Med. Chem. 45, 654-662, 2002.

10. Dutta A K,  Fei X-S, Reith M. E A. A Novel Series of Hybrid Compounds Derived By Combining 2-Aminotetralin and Piperazine Fragments: Binding Activity at D2 and D3 Receptors. Biorg. Med. Chem. Lett. 12:4:619-6, 2002.

11. . Ghorai S, Cook C. D, Davis M, Venkataraman S, Beardsley P, Reith M. E. A, Dutta A K. High affinity hydroxypiperidine analogues of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the dopamine transporter: Stereospecific interactions in vitro and in vivo. J. Med. Chem. 46, 1220-1228, 2003.

12. Dutta A K, Ghorai S, Cook C. D, Davis M, Venkataraman S, Beardsley P, Reith M. E. A. Novel trisubstituted hydroxy piperidine analogs for the dopamine transporter. Drug and Alcohol Dependence, Volume 66, Suppl 1, S2-S202, 2002.

13. Kolhatkar R B, Ghorai S K, George C, Reith M. E. A, Dutta A K. Interaction of cis-(6-benzhydryl-piperidin-3-yl)-benzyl-amine analogs with monoamine transporters: Structure Activity Relationship study of structurally constrained 3,6-disubstituted piperidine analogs of (2,2-diphenylethyl)-[1-(4-fluorobenzyl)piperidine-4-ylmethyl]amine. J. Med. Chem. 46, 2205-2215, 2003.

14. Zhang S, Reith M E A, Dutta A K. Design, synthesis, and activity of novel cis- and trans-3,6-disubstituted pyran biomimetics of 3,6-disubstituted piperidine as potential ligands for the dopamine transporter. Bioorg. Med. Chem. Lett. 13, 1591-1595, 2003.

15. Dutta A K, Zhang S, Kolhatkar R, Reith MEA. Dopamine transporter as target for drug development of cocaine dependence medications. Eur. J. Pharmacol. 479,93-106, 2003. (Invited review article)

16. Kolhatkar, R., Cook, C. D., Ghorai, S. K., Deschamps, J., Beardsley. P. M., Reith, M. E. A., Dutta, A. K. Further structurally constrained analogues of cis-(6-benzhydryl-piperidin-3-yl)-benzylamine with elucidation of bioactive conformation: Development of 1,4-diaza-bicyclo-[3,3,1] nonane derivatives and their biological characterization for the monoamine transporters systems. J. Med. Chem. 47, 5101-5113, 2004.

17. Zhang, S., Zhen, J., Reith, M. E. A., Dutta, A. K. Structural requirements for  2,4- and 3,6-disubstituted pyran biomimetics of cis-(6-benzhydryl-piperidin-3-yl)-benzylamine compounds to interact with monoamine transporters. Bioorganic Medicinal Chemistry. 12, 6301-6315, 2004.
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18. Aloke K. Dutta*, Sylesh K. Venkataraman, Xiang-Shu Fei, Rohit Kolhatkar, Shijun Zhang,  Maarten. E. A. Reith Synthesis and biological characterization of novel hybrid 7-{[2-(4-Phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol and their heterocyclic bioisosteric analogues for the dopamine D2 and D3 receptors. Bioorganic Medicinal Chemistry. 12, 4361-4373, 2004.

19. Juan Zhen, Soumen Maiti, Nianhang Chen, Aloke K. Dutta, Maarten E.A. Reith. Interaction between a hydroxypiperidine analogue of  4-(2-benzhydryloxy-ethyl)-1-(4-fluorobenzyl)piperidine  and Aspartate 68 in the human dopamine transporter. European Journal of Pharmacology, 506, 17-26, 2004.

20. Reith, M. E. A., Wang, L. C., Dutta, A. K. Pharmacological profile of radioligand binding to the norepinephrine transporter: Instances of poor indication of functional activity. J.Neurosci. Methods. 143, 87-94, 2005.
46. Shijun Zhang, Juan Zhen, Maarten E. A. Reith, and Aloke K. Dutta. Discovery of novel tri-substituted asymmetric pyran derivatives, (2S, 4R, 5R)-2-benzhydryl-5-benzylamino-tetrahydropyran-4-ol, exhibiting high affinity for serotonin and norepinephrine transporters in a stereospecific manner. J. Med. Chem. 48, 4962-4971, 2005.

21. M. Laura Parnas, Jon D. Gaffaney, Amy H. Newman, Mu-Fa Zou, John R. Lever, Aloke K. Dutta, Rohit Kolhatkar, Roxanne A. Vaughan. Dopamine transporter ligand binding domains analyzed through photoaffinity labeling. Proceedings of the North Dakota Academy of Science. 2005; 59, 52

22. Shijun Zhang, Juan Zhen, Maarten E. A. Reith, and Aloke K. Dutta. Design, Synthesis, and Preliminary SAR Study of 3- and 6-Side-Chain Extended Tetrahydro-Pyran Analogues of cis- and trans-(6-benzhydryl-piperidin-3-yl)-benzylamine. Bioorg. Med. Chem. 14, 3953-3966, 2006.

23. Shijun Zhang, Fernando Fernandez, Stuart Hazeldine, Juan Zhen, Maarten E. A. Reith, and Aloke K. Dutta. Further structural exploration of tri-substituted asymmetric pyran derivatives, (2S, 4R, 5R)-2-benzhydryl-5-benzylamino-tetrahydropyran-4-ol and their corresponding disubstituted (3S,6S) pyran derivatives: A proposed pharmacophore model for high-affinity interaction with the dopamine, serotonin and norepinephrine transporters. J. Med. Chem. 49, 4239-4247, 2006.

24. Aloke Dutta and Weidong Le. Existing Dopaminergic Therapies for Parkinson’s Disease. Expert Opinion Therapeutic Patents, 16 (12), 1613-1625, 2006. (Invited Article)

25. Swati Biswas,a Stuart Hazeldine,a Balaram Ghosh,a Ingrid Parrington,b Eldo Kuzhikandathil,c  Maarten E. A. Reithb, and Aloke K. Duttaa* “Bioisosteric heterocyclic versions of 7-{[2-(4-Phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol: Identification of highly potent and selective agonists for dopamine D3 receptor with potent in vivo activity.” J.Med. Chem, 51, 3005-3019, 2008.

26. Swati Biswas, Fernandez Fernando, Suhong Zhang, Juan Zhen, Maarten Reith and Aloke Dutta. Further structure activity relationships  study of hybrid 7-{[2-(4-Phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol  analogues : Identification of a high affinity D3-preferring agonist with potent in vivo activity with long duration of action. J. Med. Chem, 51, 101-117, 2008.

27. Prashant S. Kharkar, Maarten Reith, Aloke Dutta. “Three-Dimensional Quantitative Structure-Activity Relationship (3D QSAR) and Pharmacophore Elucidation of Tetrahydropyran Derivatives as Serotonin and Norepinephrine Transporter Inhibitors”. Journal of Computer-Aided Molecular Design, 22, 1-17, 2008.

28. Further structural optimization of cis-(6-benzhydryl-piperidin-3-yl)-benzylamine and 1,4-diazabicyclo[3.3.1]nonane derivatives by introducing exocyclic hydroxyl group: Interaction with dopamine, serotonin and norepinephrine transporters. Manoj Mishra,
Rohit Kolhatkar, Juan Zhen, Ingrid Parrington, Maarten E. A. Reith, Aloke K. Dutta. Bioorganic Medicinal Chemistry, 16, 2769-2778, 2008.

29. Pharmacological characterization of D-161, a novel triple monoamine transporter blocker: Production of antidepressant-like action. Aloke Dutta, Balaram Ghosh, Swati Biswas and Maarten Reith. European Journal of Pharmacology, 589, 73–79, 2008.

30. Dennis Brown, Prashant Kharkar, Ingrid Parrington, Maarten Reith, Aloke Dutta. Structurally constrained hybrid derivatives containing octahydrobenzo[g or f]quinoline moieties for dopamine D2 and D3 receptors: Binding characterization at D2/D3 receptors and elucidation of a pharmacophore model. J. Med. Chem. 51, 7806-7819, 2008.

31. Dennis Brown, Manoj Mishra, Suhong Zhang, Ingrid Parrington, Tamara Antonio, Maarten Reith, Aloke Dutta. Investigation of various N-heterocyclic substituted piperazine versions of 5/ 7-{[2-(4-Aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol: Effect on affinity and selectivity for dopamine D3 receptor. Bioorganic Medicinal chemistry, 17, 3923–3933, 2009.

32. Suhong Zhang, Prashant Kharkar, Ingrid Parrington, Maarten Reith, Aloke Dutta. Synthesis and characterization of  N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-N-propyl-5,6,7,8-tetrahydro-1H-naphtho [2,3-d]imidazol-6-amine related derivatives for dopamine D2/D3 receptors. Manuscript in preparation.

33. Prashant Kharkar & Aloke Dutta. Amide reversal- An underappreciated strategy in Structure-activity relationship (SAR) investigation: Insights and implications. Submitted to Journal of Chemical Information and modeling.

34. Prashant Kharkar & Aloke Dutta. Metal – Protein Attenuating Compounds (MPACs): An Emerging Approach for the Treatment of Neurodegenerative Disorders. Current Bioactive Compouds, 4, 57-67, 2008.

35. Prashant S. Kharkar[a], Angela Batman[b], Juan Zhen[c], Patrick M. Beardsley[b],
Maarten E. A. Reith[c] and Aloke K. Dutta*[a] Synthesis and biological characterization of (3R,4R)-4-(2-(benzhydryloxy)ethyl)-1-((R)-2-hydroxy-2-phenylethyl)-piperidin-3-ol and its stereoisomers for monoamine transporters. ChemMedChem, 1075-85, 2009.

36. Kyle C. Schmitt, Juan Zhen, Prashant Kharkar, Manoj Mishra, Nianhang Chen, Aloke K. Dutta and Maarten E.A. Reith. INTERACTION OF COCAINE-, BENZTROPINE-, AND GBR12909-LIKE COMPOUNDS WITH WILDTYPE AND MUTANT HUMAN DOPAMINE TRANSPORTERS: MOLECULAR FEATURES THAT DIFFERENTIALLY DETERMINE ANTAGONIST BINDING PROPERTIES. Journal of Neurochemistry, 107, 928-940, 2008.

37. Balaram Ghosh,a Prashant Kharkar, Tamara Antonio,,c  Maarten E. A. Reithb, and Aloke K. Duttaa Development of (S)-N6-Propyl-N6-(2-(4-(quinolin-5-yl)piperazin-1-yl)ethyl)- Development of (S)-N6-(2-(4-(Isoquinolin-1-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]-thiazole-2,6-diamine and its analogue as a D3 receptor preferring agonist: Potent in vivo activity in Parkinson’s disease animal models. Manuscript submitted to J. Med. Chem.

38. Balaram Ghosh,a Tamara Antonio,,c  Maarten E. A. Reithb, and Aloke K. Duttaa Discovery of 4-(4-(2-((5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)-ethyl)piperazin-1-yl)quinolin-8-ol and its analogues with dopamine D2/D3 agonists activity with a capacity to bind to iron: potential application in neuroprotective therapy for Parkinson’s Disease. Manuscript in preparation.

39. Chao Li, S. Biswas, Xingang Li, Feifei Luo, *A. K. Dutta2, *Weidong Le1; Novel multifunctional drug D-264 for Parkinson’s disease: Evidence of neuroprotective property in PD animal models induced by MPTP and lactacystin. Submitted to Neuropharmacology


FILED PATENTS

1.“Derivatives of 2-aminotetralins and Pharmaceutical Analogs thereof Exhibiting Differential CNS Receptor Behavior”. International Patent # PCT/US01/15915

2. Structure-activity studies of 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives and their N-analogs: Evaluation of potency and selectivity for monoamine transporter systems. International Patent # PCT/US01/40964

3. “A novel hybrid series of compounds derived from 2-aminotetralin and piperazine based derivatives: characterization for D1, D2, D3, D4 and serotoninergic receptor subtypes binding”. Provisional # WSU 0197 PRV.

4. Dutta, A. K. “Tri-substituted 2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-ol analogues, and novel 3,6-disubstituted pyran derivatives.” Provisional # 60/563, 189. Filed by Wayne State University.

APPROVED PATENTS

1. N- AND O-SUBSTITUTED 4-[2-(DIPHENYLMETHOXY)-ETHYL]-1-(PHENYL) METHYL) PIPERIDINE ANALOGS AND METHODS OF TREATING CNS DISORDERS THEREWITH. PATENT NO: US 6,995,268 B2; FEBRUARY 7 2006.

2. HYBRID 2-AMINOTETRALIN AND ARYL-SUBSTITUTED PIPERAZINE COMPOUNDS AND THEIR USE IN ALTERING CNS ACTIVITY. PATENT NO: US 6,982,332, JANUARY 3, 2006.

3. Derivatives of 2-aminotetralins and pharmaceutical analogs thereof exhibiting differentail cns receptor activity and behavior. Patent NO: US 7049337 B2; May 23, 2006.

 
Copyright © 2004 Wayne State University. All rights reserved.

Research Area

Our research integrates medicinal chemistry, neuropharmacology, computational chemistry and molecular biology not only to understand the mechanism of action of novel CNS active molecules but also to advance promising leads to preclinical studies. We focus on discovery of novel drugs for the CNS to explore their potential therapeutic application in several neuro-disorders like Parkinson’s disease (PD), depression and drug addiction. Specifically, novel molecules which are designed through rational drug design and computational studies, are developed routinely to target monoamine transporters and receptors systems either specifically or non-specifically to produce desired pharmacological outcome. In PD research area we are focused on development of bi or polyfunctional molecules to produce neuroprotective treatment agents. In the depression area, we have developed novel triple uptake inhibitors as promising new generation antidepressants. Our research is supported by multiple NIH R01 grants.These areas of research are currently being investigated and brief descriptions of these are given below.

Currently I am a principal investigator on two funded NIH R01 grants and in addition, I am a con-investigator in one more funded NIH R01 grants. In the past, I had two State of Michigan funding known as MUCI.

http://applebaum.wayne.edu/PSC/dutta/

Monoamine Transporters As Molecular Targets

PROJECT : In this project, we are investigating rational design, synthesis and biological evaluation of potent and selective small molecules for their binding to the biogenic amines neurotransporter systems, specifically for the dopamine transporter (DAT) system. The DAT is a putative presynaptically located 12-transmembrane domain protein which translocates extracellular dopamine into nerve endings of DA neurons. The DAT is an important constituent of brain pathways that contribute to movement and behavioral reward. Analysis of these designed molecules in various in vitro binding assays is being carried out routinely to understand their mode of binding with the transporter molecules and to build Structure-Activity Relationship studies. One of our goals is to explore the potential use of these compounds as medicating agents for the treatment of cocaine addiction and other neurological disorders. We are also engaged in developing of Single Photo Electron Computer Tomography (SPECT) and Positron Emission Tomography (PET) agents for imaging studies in the CNS, and also affinity and photo-affinity ligands as molecular probes to characterize the binding interaction with the receptors further at a molecular level to understand their functional properties. In this context, we are pursuing site directed mutagenesis study with the dopamine transporter mutants to discover point of interactions on the DAT molecule with our selective and potent ligands.

We already have generated a novel series of compounds which were found to be very selective for the dopamine transporter system from in vitro studies and exhibited interesting in vivo activity. We are also investigating bioactive receptor bound conformation of our active molecules via synthesis of conformationally constrained molecular templates to understand mode of interactions of our ligand molecules with the recognition sites in the receptor (see reference # 16). In this regard, recently we have developed, via rational drug design approach, conformationally constrained versions of our lead flexible analogues and observed interesting isomeric selectivity for their biological activity (see ref # 15). Currently, we are in the process of expanding our SAR studies to generate suitable molecules which will be used in further in vivo studies to develop medication for cocaine addiction. This study is currently funded by NIH/NIDA.

http://applebaum.wayne.edu/PSC/dutta/

Dopamine D3 receptor as molecular target

PROJECT : This project involves the design and synthesis of small molecules as selective agonist or antagonist for the dopamine receptor subtype, D3. The D3 receptor is a G-protein coupled receptor (GPCR) and carries a high degree of homology with the dopamine D2 receptor. The D3 receptor has been given considerable attention since its discovery and it is an attractive target for drug development for the following reasons: a) Unique location; b) Efficacy of existing D3-preferring agonists; c) Neuroprotective activity of D3 receptor preferring agonists; d) Antioxidant properties of D3 agonists and Possible antidepressant properties of D3 preferring ligands. We recently have developed a novel molecular template based on a hybrid drug development approach. Our SAR studies led to the development of a novel series of molecules from this template which exhibited preferential agonist activity at the D3 receptor. One of our goals is to examine possible role of neuroprotective effect mediated by activation of D3 receptor and its therapeutic application in the treatment of Parkinson’s Disease. Effect of oxidative stress is strongly implicated in PD neurodegeneration. In this regard, we plan to incorporate antioxidant activity of these molecules to observe any enhanced neuroprotective effect in animal experiments.

In order to gain further insight into molecular interaction of these hybrid molecules with the D2/D3 receptor, we plan to characterize active D3-selective enantiomerically pure compounds in D2/D3 mutants which are derived by replacing both conservative and non-conservative amino acid residues of the D3 and D2 receptors. Furthermore, we plan to carry out molecular modeling study to build a reliable pharmacophore to understand bioactive conformation of our novel agonists. The results from these studies should help us to understand whether there is a differential role of the mutated residues in contributing selective affinity for D3 over D2.

In our cell culture work, we express cloned human D2- and D3-dopamine receptors for in vitro characterization of our novel molecules. For in vivo characterization, we use 6-OH-DA induced rat model for Parkinson’s Disease. We routinely carry out anti-oxidant activity by EPR and other methods.

Therapeutic potential of selective D3-molecules in the treatment of cocaine addiction and toxicity will be explored. The application of selective D3 antagonists in the atypical treatment of Psychotic disorders will also be investigated.
This research is supported currently by a R01 grant from NIH/NINDS