Wayne State University

Aim Higher

 

Aloke Dutta, PhD

(313) 577-1064
adutta@wayne.edu

Research web site:
http://duttagroup.cphs.wayne.edu


EACPHS Room 3128

Appointments

Professor, Department of Pharmaceutical Sciences

 


Education Training

1987, 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)


Degrees and Certifications

Ph.D.


Other Experience Professional Memberships


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 Member of “Drug Discovery for the Nervous System, ZRG1 MDCN-C 91” study section, 2009-current.



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


Awards and Honors

GRANT AWARDS:

 

1. NIH/NINDS:

Title of the proposal: Novel neuroprotective treatment  for Parkinson’s Disease

Duration: 09/15/11- 6/30/16

Total Costs: $2,158,712.00

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

 

2. 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.

 

3. 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

Total Cost: $125,000

 

4. NIH/NIDA: "Dopamine transporter agents against cocaine dependence"

Duration: 09/25/2005 to 08/31/2009

Total Costs: $1,170,556

P.I.: Aloke K. Dutta

 

5. NIH/NINDS:

Title of the proposal: Novel neuroprotective treatment  for Parkinson’s Disease

Duration: 05/01/05-04/30/11

Total Costs: $1,630,166

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

 

6. 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

Total Cost: $111,195

 

7. NIH/NIDA: "Dopamine transporter agents against cocaine dependence"

Duration: 12/1/99 to 11/30/2005

Direct Costs: 1,301,923

P.I.: Aloke K. Dutta

 

8. Wayne State University Faculty Research Grant #1-41824 awarded March 4, 1999. Title of proposal:

Design and Synthesis of Novel Nitric Oxide Synthase Inhibitors

P.I.: Aloke K. Dutta, Ph.D.

Duration: May 1, 1999 –April 30, 2000

Direct costs: $7,000.00

 

9. 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

Direct Costs: $350, 000. 

P.I: Aloke. K. Dutta

 

10. University of Minnesota, Minnesota Medical Foundation

"New D1 Specific Radioligands for the Central Nervous  System".

Duration: 1989-1991. 

P.I: Aloke K. Dutta

 

 

B. Michigan Universities Commercialization Initiative (MUCI) Application

 

1. Title: Manufacture and Score 2000 Testing of WSU CNS Compounds (Dopamine Transporter Inhibitors) for use as a wake-cognition therapies

Research will be carried out with Hypnion, Inc, Worcester, MA

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

Funding period: July 2004 to August 2005

Total Cost: $52,000

 

2. 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

Total Cost: $77,246

 

3. 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

 


Recent Publications

 


PEER REVIEWED PUBLICATIONS  (From a total of 82)

 

63. Balaram Ghosh, Tamara Antonio, Juan Zhen, Prashant Kharkar,  Maarten E. A. Reith, and Aloke K. Dutta 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. J. Med. Chem. 53, 1023–1037, 2010

 

64. 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. J. Med. Chem. 53, 2114–2125, 2010.

 

65. 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. J. Neurosci. Res. 88: 2513–2523,  2010.

 

66. Angela Batman, Aloke Dutta, Patrick Beardsley. Characterising the Behavioural Effects of D-84, a selective DAT inhibitor: Potential as a Replacement Therapy for Cocaine Dependence. EJP, 648, 127–132, 2010.

 

67. Juan Zhen, Tamara Antonio, Aloke K. Dutta, Maarten E.A. Reith. Concentration of receptor and ligand revisited in a modified receptor binding protocol for high-affinity radioligands: [3H]spiperone binding to D2 and D3 dopamine receptors. J. Neurosci. Methods. 188, 32-38, 2010.

 

68. Kyle C Schmitt, Sreeman Mamidyala, Swati Biswas, Aloke K Dutta and Maarten EA Reith*. Bivalent Phenethylamines as Novel Dopamine Transporter Inhibitors: Evidence for Multiple Substrate-Binding Sites in a Single Transporter. J. Neurochem. 112, 1605–1618, 2010.

 

69. Balaram Ghosh, Tamara Antonio, Bhaskar Gopishetty, Maarten Reith, Aloke Dutta. Further delineation of hydrophobic binding sites in dopamine D2/D3 receptors for N-4 substituents on the piperazine ring of the hybrid template 5/ 7-{[2-(4-Aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ol. Bioorganic Medicinal Chemistry. 18, 5661–5674, 2010.

 

70. Sandhya Kortagere, Shu-Yuan Cheng, Tamara Antonio, Juan Zhen, Maarten E.A. Reith, and Aloke K. Dutta. Interaction of novel hybrid compounds with the D3 dopamine receptor: Site directed mutagenesis and homology modeling studies. Biochemical Pharmacology 81, 157–163, 2011.

 

71. Dopamine D2/D3 agonist with potent iron chelation, antioxidant and neuroprotective properties: Potential implication in symptomatic and neuroprotective treatment of Parkinson’s disease. Sanjib Gogo, Tamara Antonio, Subramanian Rajagopalan, Maarten Reith, Julie Andersen, Aloke K. Dutta*. ChemMedChem. 6, 991-5, 2011.

 

72. Further structure activity relationship studies on 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: Identification of compounds with triple uptake inhibitory activity as potential antidepressant agents. Bhaskar Gopishetty, Stuart Hazeldine, Soumava Santra, Mark Johnson, Gyan Modi, Solav Ali, Juan Zhen,  Maarten Reith  Aloke Dutta. J. Med. Chem. 54, 2924-32, 2011.

 

73. The novel trisubstituted pyran derivative D-142 with triple monoamine reuptake inhibitory activity: potent antidepressant-like activity from animal models of depression studies. Aloke K. Dutta, Bhaskar Gopishetty, Sanjib Gogoi,  Solav Ali, Juan Zhen, Maarten Reith. European Journal of Pharmacology, 671, 39–44, 2011.

 

74. Development of an efficient asymmetric synthetic route to a novel triple uptake inhibitor antidepressant (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol (D-142). Bhaskar Gopishetty, Sanjib Gogo, Aloke Dutta. Tetrahedron Asymmetry. 22 1081–1086, 2011.

 

75. Juan Zhen, Solav Ali, Aloke K. Dutta, Maarten E.A. Reith. [3H]CFT can bind to the norepinephrine transporter with pharmacological relevance. J Neurosci Meth. 15; 203(1):19-27, 2012.

 

76. Novel bivalent ligands for D2/D3 dopamine receptors: Significant co-operative gain in D2 affinity and potency. Sanjib Gogoi, Swati Biswas, Antonio Tamara, Maarten Reith, Aloke Dutta. ACS Med Chem Lett. ;3(12):991-996, 2012.

 

77. Structural Exploration of (3S,6S)-6-Benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine Analogues: Identification of Potent Triple Monoamine Reuptake Inhibitors as Potential Antidepressants.. Sanjib Gogoi, Soumava Santra, Bhaskar Gopishetty, Tamara Antonio, Juan Zhen,  Maarten Reith,  Aloke Dutta. ChemMedChem, 2012 Dec;7(12):2093-100

 

78. D-514, a multifunctional pro-drug with motor stimulating and neuroprotective properties: Possible neuroprotective treatment agent for Parkinson’s disease. Sanjib Gogoi, Asawari Lote, Tamara Antonio, Maarten Reith, Aloke Dutta. Manuscript in preparation.

 

79. Structure activity relationship study of N6-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)-N6-propyl-4, 5, 6, 7-tetrahydrobenzo[d]thiazole-2, 6-diamine analogues: Development of highly selective D3 dopamine receptor agonists along with highly potent D2/D3 agonist and their pharmacological characterization. Mark Johnson, Tamara Antonio, Maarten Reith, Aloke Dutta. J. Med. Chem. 55, 5826-40, 2012.

 

80. Interaction of D3 preferring agonist (─)-N6-(2-(4-(Biphenyl-4-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264) with cloned human D2L, D2S and D3 receptors: Potent stimulation of mitogen-activated protein kinases and G-protein coupled inward rectifier potassium channels. Eldo Kuzhikandathil, Samantha Cote, Soumava Santra, Aloke K. Dutta. Naunyn-Schmiedeberg's Archives of Pharmacology, 386(2):97-105, 2013.

 

81. D-512, a novel highly potent dopamine D2/D3 agonist and D-440, a novel highly selective D3 receptor agonist: Assessment of neuroprotection properties in dopaminergic cell lines and evaluation of in vivo activity in PD animal model. Soumava Santra, Mark Johnson, Liping Xu, Aloke Dutta. Manuscript Submitted.

 

82. Approach towards development of multifunctional drugs as an effective strategy for treatment of Parkinson’s disease. Soumava Santra,1 Liping Xu,1 , Mark Johnson,1 Sanjib Gogoi,1 Tamara Antonio,2 Maarten E. A. Reith,2, Aloke K. Dutta1* Catecholamine Proceedings, In Press.

 

 

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.”, WSU 0203PUSA.

 

5. 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  U.S. Patent Appn. No. 12/770,079 (WSU 0197 PUSA2). Status:  Pending, no action yet

Filing Date:  April 29, 2010.

 

6. WSU 0210 Patent Family. Title:            BIFUNCTIONAL/POLYFUNCTIONAL DOPAMINE D2/D3 AGONIST AS NEUROPROTECTIVE AGENTS FOR TREATMENT OF

NEURODEGENERATIVE DISEASES, WSU 0210 PCT, PCT/US2010/031900, April 2010.

 

 

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.

 

4. N-AND O-SUBSTITUTED 4-[2-( DIPHENYLMETHOXY) -ETHYL]-1- (PHENYL) METHYL) PIPERIDINE ANALOGS AND METHODS OF TREATING CNS DISORDERS THEREWITH. U.S. Pat. No. 7,595,331, September 29, 2009.

 

5. HYBRID 2-AMINOTETRALIN AND ARYL-SUBSTITUTED PIPERAZINE COMPOUNDS AND THEIR USE IN ALTERING CNS ACTIVITY . U.S. Patent Appn. No. 11/235612 (WSU 0197 PUSA1). Status:  Patented as U.S. Pat. No. 7,723,519.  Issue Date:  May 25,

2010.

 

6. 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.”, WSU 0203PUSA, U.S. Pat. No. US7,915,433 B2, March 29, 2011.

 

7. 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.”, WSU 0203PUSA, U.S. Pat. No. US8,017,791, September 13, 2011.

 

 

 

 

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.

2. Johnson, Mark and Dutta, A. K. Dopamine D3 receptor preferring agonists and antagonists as anti-Parkinsonian agents. Edited by Ana Martinez, RSC publication, 2012.

 


Primary Research Title

Research Area


Primary Research Interest

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.

 


Primary Research Link

http://duttagroup.cphs.wayne.edu/


Secondary Research Title

Monoamine Transporters As Molecular Targets


Secondary Research Interest

In this project, we have been developing via asymmetric synthesis process, novel asymmetric unique pyran templates as blockers for serotonin (SERT), norepinephrine (NET) and dopamine (DAT) transporters. Our initial work on development of asymmetric di- and tri-substituted pyran derivatives identified potent triple uptake inhibitors (TUI) as blocker of SERT, DAT and NET as well as selective blockers for NET. Asymmetric synthesis methods have been developed by us to generate these molecules. Some of our lead asymmetric pyran derivatives exhibited SNRI type profile by being potent at both SERT and NET. In addition, compounds with selective affinity for the NET (Ki; NET: 4.92 nM, DAT/NET = 91, SERT/NET = 140) were also discovered. Our central hypothesis in this project is to evaluate whether the inclusion of additional dopaminergic activity in these TUI will enhance their antidepressant activity as dopamine has been strongly linked to depression. One of our goals will be to study whether such novel TUI molecules can produce more desirable therapeutic profiles as antidepressant agents compared to the current existing drugs and whether their chronic exposure lead to the production of neurotrophic factors e.g. BDNF, in the CNS via gene expression. This project is funded by a R01 NIH/NIMH grant.


Third Research Title

Dopamine D3 receptor as molecular target


Third Research Interest

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


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