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 97)

 

From 2006-Current

 

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.

 

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.

 

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

 

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.

 

 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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

Prashant S. Kharkar, Angela Batman, Juan Zhen, Patrick M. Beardsley,

Maarten E. A. Reith and Aloke K. Dutta* 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.

 

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.

 

 

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.

 

Balaram Ghosh, Tamara Antonio,,  Maarten E. A. Reith, and Aloke K. Dutta. 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.

 

Chao Li, S. Biswas, Xingang Li, Feifei Luo, *A. K. Dutta, *Weidong Le:  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.

 

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.

 

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.

 

Juan Zhen, Solav Ali, Aloke K. Dutta, Maarten E.A. Reith. [3H]CFT can bind to the norepinephrine transporter with pharmacological relevance. Manuscript submitted to JPET.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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

 

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.

 

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.

 

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.

 

D-512 and D-440 as novel multifunctional dopamine agonists: Characterization of neuroprotection properties and evaluation of in vivo efficacy in a Parkinson’s disease animal model. Soumava Santra, Liping Xu, Mrudang Shah, Mark Johnson and Aloke Dutta. ACS Chem. Neurosci., 4 (10), pp 1382–1392, 2013.

 

Soumava Santra,1 Liping Xu,1 , Mark Johnson,1 Sanjib Gogoi,1 Tamara Antonio,2 Maarten E. A. Reith,2, Aloke K. Dutta1*  (2013). .  Approach towards development of multifunctional drugs as an effective strategy for treatment of Parkinson’s disease. In L. Eiden (Ed.), Catecholamine Research in the 21st Century: Abstracts and Graphical Abstracts, 10th International Catecholamine Symposium 2012, 148-149, Oxford, UK: Elsevier.

 

Bhaskar Gopishetty, Suhong Zhang, Prashant S. Kharkar, Tamara Antonio, Maarten Reith, Aloke K. Dutta. Modification of agonist binding moiety in hybrid derivative 5/ 7-{[2-(4-Aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/ -2-amino versions: Impact on functional activity and selectivity for dopamine D2/D3 receptors. Bioorganic & Medicinal Chemistry 21, 3164–3174, 2013.

 

Gyan Modi, Tamara Antonio, Maarten Reith, Aloke Dutta. Structural Modifications of Neuroprotective Anti-Parkinsonian (−)N6(2-(4-(Biphenyl-4-yl)piperazin-1-yl)-ethyl)N6propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264): An Effort toward the Improvement of in Vivo Efficacy of the Parent Molecule. J. Med. Chem. 2014, 57, 1557−1572.

 

High affinity D2/D3 agonist D512 protects PC12 cells from 6-OHDA induced apoptotic cell death and rescued dopaminergic neurons in the MPTP mouse model of Parkinson’s disease. Mrudang Shah, Chandrasekhar Voshavar, Liping Xu, Subramanian Rajagopalan, Julie Andersen, Aloke Dutta. Journal of Neurochemistry. Volume 131, Issue 1, 74–85, 2014.

 

Flexible and biomimetic analogs of triple uptake inhibitor 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol : Synthesis, biological characterization, and development of a pharmacophore model

Horrick Sharma,1 Soumava Santra,1 Joy Debnath,1 Bhaskar Gopishetty,1 Tamara Antonio,2 Maarten Reith,2,3 and Aloke Dutta1*. Bioorganic & Medicinal Chemistry 22 (2014) 311–324.

 

Development of potent dopamine-norepinephrine uptake inhibitors (DNRI) based on (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol molecular template. Soumava Santra, Horrick Sharma, Seenuvasan Vedachalam, Tamara Antonio, Maarten Reith, Aloke Dutta. Manuscript submitted to Bioorganic & Medicinal Chemistry.

 

Triple Uptake Inhibitor as a potential new generation antidepressant agents. Soumava Santra, Horrick Sharma and Aloke Dutta. An invited review under preparation. Future Medicinal Chemistry.

 

Dopamine D3 agonists in the Treatment of Parkinson's Disease. Banibrata Das, Gyan P. Modi, Aloke K. Dutta. Current Topics in Medicinal Chemistry (An invited review), In Press.

 

 

Multifunctional D2/D3 agonist D-520 with high in vivo efficacy: Modulator of toxicity of Alpha synuclein aggregates. Gyan Modi, Chandrashekhar Voshavar, Mrudang Shah, Tamara Antonio, Maarten Reith, Aloke Dutta. ACS Chem. Neurosci., 2014, 5 (8), pp 700–717.

 

Understanding the Structural Requirements of Hybrid (S)-6-((2-(4-Phenylpiperazin-1-

yl)ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol and its Analogs as D2/D3 Receptor Ligands: A Three-Dimensional Quantitative Structure-Activity Relationship (3D QSAR) Investigation. Gyan Modi, Horrick Sharma, Prashant Kharkar, Aloke Dutta. Med. Chem. Commun., 2014, 5, 1384–1399

 

Pharmacological and behavioral characterization of an orally active triple reuptake inhibitor D-473: Effects of drug on extracellular levels of dopamine, serotonin and norepinephrine. Aloke Dutta, Soumava Santra, Horrick Sharma, Omar Mabrouk, Tamara Antonio, Maarten Reith. Plos One, In Press.

 

 

 

 

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.

 

8. HYBRID 2-AMINOTETRALIN AND ARYL-SUBSTITUTED PIPERAZINE COMPOUNDS AND THEIR USE IN ALTERING CNS ACTIVITY. PATENT NO: US 8,227,604 B2, July 24, 2012.

 

9. 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. US8,519,159 B2, August 27, 2013.

 

10. Dutta, A. K. “TRI-SUBSTITUTED 2-BENZHYDRYL-5-BENZLAMINO-TETRAHYDRO-PYRAN-4-OL AND 6-BENZHYDRYL-4-BENZYLAMINO-TETRAHYDRO-PYRAN-3-OL ANALOGUES, AND NOVEL 3,6-DISUBSTITUTED PYRAN DERIVATIVES”. European Pat. No. EP 1 976 381 B1, July 24, 2013.

 

11. Dutta, A. K. “TRI-SUBSTITUTED 2-BENZHYDRYL-5-BENZLAMINO-TETRAHYDRO-PYRAN-4-OL AND 6-BENZHYDRYL-4-BENZYLAMINO-TETRAHYDRO-PYRAN-3-OL ANALOGUES, AND NOVEL 3,6-DISUBSTITUTED PYRAN DERIVATIVES”. European Pat. No. EP 1 734948 B1, June 11, 2014.

 

12. 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. U.S. Pat. No. US 8,841,464, September 23, 2014.

 

 

FILED PATENTS

 

1. 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.

 

2. 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.

 


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 CNS drugs 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 being developed routinely to target monoamine transporters and receptors systems either selectively or non-selectively to produce desired pharmacological response. In PD research area we are focused on development of bi or polyfunctional molecules to produce disease modifying neuroprotective treatment agents. In this regard, we are designing multifunctional D2/D3 and D3 preferring agonists by incorporating metal chelation and anti-oxidant properties along with inhibitory activity against alpha-synuclein protein aggregation in these molecules to address complex pathogenesis of PD including oxidative stress. Our overall goal in this project is not only to address symptomatic (relieving motor dysfunction) factor of this disease but also to produce disease modifying neuroprotective effects to slow or stop the progression of the disease. In the depression area, we have developed novel triple uptake inhibitors as promising new generation antidepressants addressing anhedonia in MDD. One of our main thrust in our research is to develop multifunctional molecules as a novel approach to CNS drug discovery and development. Our research is supported by multiple NIH R01 grants.

 


Primary Research Link

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


Secondary Research Title

NOVEL NEUROPROTECTIVE THERAPY FOR NEURODEGENERATIVE DISEASES


Secondary Research Interest

PROJECT # 1:  

Pathogenesis of PD and neurodegeneration in general is complex. Growing body of literature suggest that suitable multifunctional drugs might be more effective to act as disease modifying agents than drugs that target single functional component. In this regard, our multifunctional drugs which combine dopamine D2/D3 agonist property or D3 preferring agonist property along with addressing other pathogenic factors of PD will have the potential to slow or stop the disease progression while being symptomatically beneficial in alleviating motor dysfunction.

Effect of oxidative stress is strongly implicated in PD neurodegeneration. In this regard, we have been developing polyfunctional agonist molecules, which, along with their agonist activity, also should complex to metal ion like iron. Role of Iron, alpha synuclein protein aggregation and oxidative stress have been implicated strongly in the pathogenesis of PD. Our multifunctional properties include antioxidant activity, iron chelation activity, Increase of cellular GSH/ catalase level, increase of UPS level and inhibition of alpha-synuclein protein aggregation.

One of our ongoing projects involves the design and synthesis of multifunctional small molecules as potent agonists at the dopamine receptor subtype, D3 and D2. We have developed a novel molecular template based on a hybrid drug development approach. Further SAR studies led to the development of a series of agonist molecules from this novel template. One of our goals is to examine possible role of D3 receptor activation in the production of neuroprotective effect via expression of neurotrophic factors (BDNF & GDNF) and its effect in the treatment of Parkinson’s disease (PD). Recently, we published a paper demonstrating neuroprotective property of lead multifunctional D2/D3 agonist with high potency (J. Neurosci. Res. 88: 2513–2523,  2010, ACS Chem. Neurosci. 4 (10), pp 1382–1392, 2013, J. Neurochemistry, Volume 131, Issue 1, 74–85, 2014).  In parallel, we are designing multifunctional D2/D3 and D3 preferring agonists by incorporating metal chelation and anti-oxidant properties along with inhibitory activity against alpha-synuclein protein aggregation in these molecules to address complex pathogenesis of PD including oxidative stress. Our overall goal in this project is not only to address symptomatic (relieving motor dysfunction) factor of this disease process but also to produce disease modifying neuroprotective effects to slow or stop the progression of the degeneration process. We have recently published articles on iron binding D2/D3 agonists to demonstrate validity of our proof of concept (J. Med. Chem. 53, 2114–2125, 2010; ChemMedChem. 6, 991-5, 2011). We have also recently published an article based on our proof of concept preliminary data from a lead multifunctional D2/D3 agonists with property to modulate aggregation of alpha synuclein protein (ACS Chem. Neurosci, ACS Chem. Neurosci., 2014, 5 (8), pp 700–717). I have been awarded a competing renewal funding by R01 NIH/NINDS for another five years to continue our research work in this project.

 

Therapeutic potential of selective D3-molecules in the treatment of cocaine addiction and toxicity are being explored. The application of selective D3 antagonists in the atypical treatment of Psychotic disorders will also be investigated.

 

 


Third Research Title

TRIPLE UPTAKE INHIBTOR AS NOVEL MODULATORS OF DEPRESSION AND PAIN


Third Research Interest

PROJECT # 2

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 (TRI) as blocker of SERT, DAT and NET as well as selective dopamine-norepinephrine reuptake inhibitors (DNRI). Asymmetric synthesis methods have been developed by us to generate these novel molecules. 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 major depressive disorder (MDD). Some of our selected publications in this area are J. Med. Chem. 48, 4962-4971, 2005; EJP, 589, 73–79, 2008; EJP, 671, 39–44, 2011; ChemMedChem, 7(12):2093-100, 2012; Bioorganic & Medicinal Chemistry 22 (2014) 311–324). In one of our recent publications, we have demonstrated development of an orally active TRI (Plos One, 2014, 9, e113420). One of our important goals will be to study whether such novel TRI molecules can address anhedonia, a major unmet need in the current treatment of MDD, which accounts for their inefficacy. Thus, TRI can potentially serve as a new generation antidepressants by producing more desirable therapeutic profiles compared to the current existing drugs. Our drug discovery effort in this project integrates studies, which include chemistry, in vitro and in vivo pharmacology, Positron Emission Tomography (PET) imaging and new generation animal depression models. I have been funded by a R01 (NIH/NIMH) grant based on this project. We are currently working on towards a competing renewal of our grant.


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