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Dopamine D3 Receptors and Parkinson’s Disease: Unraveling a Biased Story

Wednesday, May 15, 2019

4:00 PM-5:30 PM

BIOMED Seminar

Dopamine D3 Receptors and Parkinson’s Disease: Unraveling a Biased Story

Sandhya Kortagere, PhD
Associate Professor
Department of Microbiology and Immunology
Drexel University College of Medicine

Dopamine (DA) receptors play a major role in brain and periphery in controlling several physiological functions such as motor, cognitive, arousal, muscle rigidity, hormonal and blood flow regulation. These functions are mediated by tightly coordinated signaling pathways that include the heterotrimeric G-proteins, second messengers, and a relay of kinases and phosphatases. Hence, it is not surprising that dopamine receptors are major drug targets for treating neuropsychiatric disorders, such as schizophrenia, Parkinson’s disease (PD), depression, and bipolar disorders. The five DA receptors are classified into two sub-classes based on their pharmacological properties as D1-like (D1, D5 receptors) and D2-like (D2, D3 and D4 receptors). These receptor sub-types not only share a structural homolog, but also localize in the same regions of the brain. As a result, drugs developed to target these receptors often lack selectivity and specificity to a given DA receptor, thus leading to severe side effects. Dopamine D3 receptors (D3Rs) have been recently implicated in several neuronal disorders, including PD and addiction.

Treatment complications, such as L-dopa induced dyskinesia and impulsive and compulsive behaviors, have been shown to be strongly correlated with D3R agonist activity. However, the exact mechanism by which D3R mediates these behaviors have not been established due to lack of D3R selective agonists. We have recently developed SK609, which is a G-protein biased signaling agonist of D3R, and demonstrated its efficacy in improving the motor symptoms of PD in a rodent model. In addition, SK609 under chronic treatment conditions does not produce dyskinesia side effects and when co-administered with Levodopa blocks abnormal involuntary movements associated with L-dopa induced dyskinesia. These contradicting observations lead us to hypothesize that unbiased or β-arrestin biased agonists of D3R promote dyskinesia and impulsive behaviors, while G-protein biased agonists of D3R produce improvement in motor and cognitive impairment in PD. Current research in our laboratory is directed towards understanding the basic signaling mechanisms between biased and unbiased ligands of D3R and their effects on motor and cognitive behavioral tasks.

Sandhya Kortagere, PhD, is an Associate Professor in the Department of Microbiology and Immunology and holds a secondary appointment in the Department of Pharmacology and Physiology, both at the Drexel University College of Medicine. She is also a co-founder and acting chief scientific officer of Polycore Therapeutics LLC. Prior to her arrival at Drexel in 2008, Dr. Kortagere was a research and teaching specialist at Robert Wood Johnson Medical School of Rutgers University, NJ. In 2003, Dr. Kortagere obtained her PhD at the National Institute of Mental Health and Neurosciences, Bangalore, India in Molecular Pharmacology and pursued a postdoctoral fellowship at Mount Sinai Medical Center and Weill Cornell Medical College in New York City.

Dr. Kortagere has published over 50 peer reviewed papers, 3 book chapters, and edited a book “In Silico Models for Drug Discovery." Dr. Kortagere is a well-trained molecular pharmacologist with over 17 years of experience in drug discovery and pharmacology of dopamine receptors. She developed a platform technology called Hybrid Structure Based Method to design small molecule modulators for a variety of therapeutically relevant protein targets.

Dr. Kortagere is interested in designing and developing small-molecule modulators to treat neurodegenerative diseases. Her laboratory is specifically interested in biased signaling and functional selectivity of Dopamine D3 receptor agonists. Her work has demonstrated that biased signaling agonists can be used to attenuate abnormal involuntary movements associated with levodopa induced dyskinesia without impacting the efficacy of levodopa to treat motor impairment in rodent models of Parkinson’s disease. Dr. Kortagere's laboratory is also interested in understanding the etiology of impulsive and compulsive behaviors, neuroinflammation and neurodegeneration, and developing symptomatic and disease modifying therapies for Parkinson’s disease.

Contact Information

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