Developing New Dopamine D2 Receptor Agonists and Partial Agonists for Parkinson’s Disease and Schizophrenia

Abstract

Parkinson’s disease (PD) and schizophrenia are neuropsychiatric disorders that affect millions worldwide. Current medications target the dopamine D2 receptor (D2R). However, adverse side effects associated with these medications significantly reduce quality of life and drug compliance. Thus, new therapeutic strategies are clearly needed. D2R activation by agonists can activate cAMP and ß‐arrestin signaling pathways in neurons. Current evidence suggests that new biased D2R agonists—which preferentially activate one pathway over the other—and new D2R partial agonists could provide greater treatment specificity and avoid side effects. In order to develop new D2R‐selective agonists and partial agonists with potential biased signaling properties, new structural templates are needed. The objective of this project is to identify and investigate new D2R ligands with novel chemical scaffolds, with the long‐term goal of producing more effective medications for neuropsychiatric disorders. An initial virtual screen of a ZINC lead‐like library with >3.6 million molecular structures was performed using models of the D2R crystal structure refined into unbiased agonist and G protein‐biased agonist biding modes via molecular dynamics simulations. Following this in silico screen, 8 potentially novel D2R ligands were purchased and tested in radioligand competition binding screens using [3H]N‐methylspiperone and [3H]7‐OH‐DPAT. 6 of 8 purchased compounds (A01, A02, A03, A08, B03, B06) have detectable affinity for D2R (Ki = 0.75–51 μM), demonstrating the feasibility of our approach. New molecular dynamics simulations have been completed to expand in silico screens to include partial agonist and β‐arrestin‐biased agonist binding modes, and to evaluate a larger ZINC library (>17.9 million structures). Studies are ongoing to determine Ki values at D3R and D4R, and to characterize compound efficacy in cAMP and β‐arrestin signaling pathways for each hit compound. Collaborations are in development to build initial analogue libraries of each compound. Each hit compound is a new structural entity with no previously known dopaminergic activity. The identification of new chemical entities with D2R activity will build the foundation for future research to optimize pharmacological parameters for preclinical medications development.Support or Funding InformationThis research is supported by the Rowan University College of Science & Mathematics SEED Fund and the New Jersey Health Foundation. Travel support is provided by the Dean of the College of Science & Mathematics and the Rowan University Provost’s Office.