• Institutional Service Award, Drexel University College of Medicine (2024)
• Provost Solutions Fellow, Drexel University (2022-23)

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 receptor agonists and allosteric modulators of catecholamine transporters.

Research Staff and Students

Research scientist: Dr. Wei Xu
Postdoctoral fellows: Dr. Frank Bearoff; Dr. Sanjay Das
Graduate students: Matthew Ritts – 2nd year PhD in MCBG program; Kyle McCloskey – 1st year MD student (summer research)

Research: Parkinson’s disease (PD) is a chronic and progressive neurological disorder affecting nearly 1 million people over the age of 60 in the U.S. and over 6 million people globally. Patients generally suffer from motor as well as a range of non-motor symptoms arising from the disease and treatment complications. Currently, there are no drugs on the market that can halt or reverse the progression of the disease. Levodopa is a gold standard for treating motor symptoms, but long-term usage leads to painful motor complications manifesting as Levodopa-induced dyskinesia (LID). Other treatment complications include development of tolerance, “ON-OFF” effects and worsening of several non-motor symptoms. Our laboratory is interested in understanding the neurobiological basis for LID, mild cognitive impairment (PD-MCI), and impulsive and compulsive behaviors associated with dopaminergic therapeutics.

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Biased signaling agonists to treat Levodopa-induced dyskinesia: The molecular mechanisms underlying the development of LID in PD are not well understood. LID is accompanied by a number of molecular changes including alterations in the levels and signaling of D1R, D2R and D3R receptors. In addition, we and others have hypothesized the role of D1R-D3R crosstalk in the dorsal striatum as one of the contributing factors to the etiology of LID. Our laboratory has recently demonstrated that SK609 a biased signaling agonist of D3R is effective in reducing the severity of LID when co-administered with Levodopa. We are currently testing the mechanism of action of SK609 in LID and its role in promoting D1R-D3R crosstalk in the dorsal striatum.

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Disease modifying therapies for Parkinson’s disease: Despite several advances in developing therapeutics for PD, there are no drugs to halt or reverse the progression of the disease. In an effort to reduce neurodegeneration, our laboratory has developed two distinct classes of small molecules that target two signaling pathways but both culminating in neuroprotection and blocking neurodegeneration. The orally available KA592 is designed to block inflammatory pathways that promote sustained inflammation and GT951 and its analogs are designed to reduce excitotoxicity in PD.

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Excitotoxicity in PD: Loss of dopaminergic neurons in the substantia nigra pars compacta in PD leads to a cascade of events including an increase in extracellular glutamate levels resulting in hyperactivation of the glutamate receptors in the basal ganglia. Hyperactive glutamate receptors trigger activation of pathways that alter cell-cell interactions and produce toxic reactive oxygen species that affect the cell viability and neurodegeneration. We have recently designed a series of positive allosteric modulators of glutamate transporter – GLT1 (also called EAAT2) with high specificity to these transporters. We hypothesize that selective activation of GLT1 by our novel allosteric modulators can remove excess glutamate from the synapse thereby reducing excitotoxicity without inducing other glutamate receptor mediated toxic events. Blocking excitotoxicity has been shown to promote neuroprotection in PD. Our laboratory is currently evaluating these effects in a rodent model of PD.

Other interesting projects: Since the design of the HSB method a novel small molecule screening platform, we have designed small molecule modulators to a number of targets including HIV capsid, protein-protein interactions in Plasmodium falciparum and Toxoplasmosis gondii. Our pyrazole amide molecule 21A092 was licensed by medicines for malaria venture (MMV) and is currently in preclinical development.

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"New Drug Could Treat Parkinson's"
Pulse (Fall 2015)

"Invented Here"
Exel (2015)

Selected publications:

“Limitations of the rat medial forebrain lesion model to study prefrontal cortex mediated cognitive tasks in Parkinson's disease”
Marshall CA, King KM, Kortagere S
Brain Res.. pii: S0006-8993(18)30178-1, Mar 30, 2018

“Functional Characterization of a Novel Series of Biased Signaling Dopamine D3 Receptor Agonists”
Xu W, Wang X, Tocker AM, Huang P, Reith ME, Liu-Chen LY, Smith III AB, Kortagere S
ACS Chem Neurosci.; 8(3); 486-500, 2017

“In vivo characterization of a novel Dopamine D3 agonist to treat motor symptoms of Parkinson’s Disease”
Simms SL, Heuttner DP, Kortagere S
Neuropharmacology, 100; 106-15, 2016

“Identification of Novel Allosteric Modulators of Glutamate Transporter EAAT2”
Kortagere S, Mortensen OV, Xia J, Lester W, Fang Y, Srikanth Y, Salvino JM, Fontana ACK
ACS Chem Neurosci; 9(3); 522-534, 2018

“Pyrazoleamide Compounds are Potent Antimalarials that Target Na+ Homeostasis in Intraerythrocytic Plasmodium falciparum”
Vaidya AB, Morrisey JM, Zhang Z, Das S, Daly TM, Otto TD, Spillman NJ, Wyvratt M, Seigl P, Marfurt J, Wirjanata G, Sebayang BF, Price RN, Chatterjee A, Nagle A, Stasiak M, Charman SA, Angulo-Barturen I, Ferrer S, Jiménez-Díaz MB, Martinez MS, Gamo FJ, Avery VM, Ruecker A, Delves M, Kirk K, Berriman M, Kortagere S, Burrows J, Fan E, Bergman LW
Nature Commun; 5; 5521, 2014

“Identification of an allosteric modulator of the serotonin transporter with novel mechanism of action”
Kortagere S, Fontana AC, Rose DR, Mortensen OV
Neuropharmacology; 72: 282-90, 2013

“An Amino Acid Residue in the Second Extracellular  Loop  Determines  the  Agonist-Dependent  Tolerance  Property  of  the  Human  D3 Dopamine Receptor”.
Gil-Mast S, Kortagere S, Kota K, Kuzhikandathil EV.
ACS Chem Neurosci, 4(6); 940-51, 2013

"Identification and characterization of a novel class of atypical dopamine receptor agonists"
Kuzhikandathil EV, and S Kortagere
Pharm. Res, 29(8): 2264-2275, 2012

"Interaction of novel hybrid compounds with the D3 dopamine receptor: Site-directed mutagenesis and homology modeling studies"
Kortagere S, Cheng SY, Antonio T, Zhen J, Reith ME, and AK Dutta
Biochem. Pharmacol, 81(1): 157-163, 2011

"Structure-based design of novel small-molecule inhibitors of Plasmodium falciparum"
Kortagere S, Welsh WJ, Morrisey JM, Daly T, Ejigiri I, Sinnis P, Vaidya AB, and LW Bergman
J. Chem. Inf. Model, 50(5) :840-849, 2010

"Development of tolerance in D3 dopamine receptor signaling is accompanied by distinct changes in receptor conformation"
Westrich L., Gil-Mast S., Kortagere S., and E. V. Kuzhikandathil.
Biochemical Pharmacology, 79(6): 897-907, 2010

"The importance of discerning shape in molecular pharmacology"
Kortagere S., Krasowski M. D., and S. Ekins
Trends in Pharmacological Sciences, 30(3): 138-147, 2009

"New Predictive Models for Blood-Brain Barrier Permeability of Drug-like Molecules"
Kortagere S., Chekmarev D., Welsh W.J., and S. Ekins
Pharmaceutical Research, 25(8): 1836-1845, 2008

"Development and application of hybrid structure based method for efficient screening of ligands binding to G-protein coupled receptors"
Kortagere, S., and W. J. Welsh
Journal of Computer-Aided Molecular Design, 20(12): 789-802, 2006

"Ab initio computational modeling of loops in G-protein-coupled receptors: lessons from the crystal structure of rhodopsin"
Mehler E.L., Hassan S. A., Kortagere S., and H. Weinstein
Proteins, 64(3): 673-690, 2006

"Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain" 
Kortagere S., Gmeiner P., Weinstein H., and J.A. Schetz.
Molecular Pharmacology, 66(6): 1491-1499, 2004