Identification of a novel, highly potent D3 dopamine receptor‐selective agonist (662.8)

Abstract

Dopamine receptors (DARs) are involved in the development and/or treatment of many neuropsychiatric disorders including schizophrenia and Parkinson’s disease. Many currently available dopaminergic drugs modulate both D2 and D3 DARs due to high homology in their orthosteric binding sites, leading not only to potential unwanted side effects, but also uncertainty as to the roles each DAR subtype plays in normal and pathological processes. In order to discover compounds that target unique, less conserved allosteric sites of these DARs, our lab employed a high throughput screening approach. Through the NIH Molecular Libraries Program, compound 3843 was originally identified as a D2 antagonist in a screen of a 380,000+ small molecule library. Counter‐screening assays of beta‐arrestin recruitment revealed that this compound selectively activates the D3 DAR, yet also acts as an antagonist at the D2 DAR. Over 270 analogs were synthesized and tested to explore the structure‐activity relationship of 3843 for the D2 and D3 DARs, and several compounds with a 1,000‐fold or greater increase in D3 DAR agonist potency were found. Initial competition binding assays suggest these compounds act in an allosteric manner at the D3 DAR, and initial ADME studies performed on 3843 were favorable. We ultimately hope these probes will be useful in vitro and in vivo pharmacological tools to elucidate D3 DAR specific physiology and pathology.Grant Funding Source: Supported by NIH IRP