Discovery, characterization, and optimization of highly selective D2 dopaminergic antagonists

Abstract

The D2 dopamine receptor (DAR) is central in the etiology and/or therapy of many neuropsychiatric disorders. Unfortunately, truly specific drugs for this receptor have been difficult to obtain, primarily due to high conservation of the orthosteric binding site within DAR subtypes and other G protein‐coupled receptors (GPCRs). In order to develop novel molecular scaffolds for the D2 DAR, we used high throughput screening to interrogate a small molecule library and identify hit ligands with distinct functional characteristics, mechanisms of action, and selectivity among DAR subtypes. Here we present the discovery of a novel series of small molecule selective D2 DAR antagonists found in this campaign. One such hit was optimized via medicinal chemistry efforts, and a lead compound was identified with high D2 selectivity versus D1, D3, D4 and D5 DARs. Interestingly the binding of this compound to the D2 DAR demonstrated near complete dependence on Na+. Furthermore, the lead compound showed favorable ADME and in vivo pharmacokinetic (PK) properties. In a profiling screen of a large panel of GPCRs the compound showed relatively low cross reactivity. This probe could be a useful pharmacological tool for studying structure activity relationships with the help of computational docking and simulations, as well as an ideal scaffold for the further development of even more highly selective D2 DAR compounds.