Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D₃-Selective Antagonists.

ABSTRACT: Previous studies have confirmed that the binding of D₃ receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D₃ receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D₃ receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D₃ receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D₃ receptor affinities (Ki = 0.8-13.2 nM) with subtype selectivity to the D₂ receptor ranging from 22- to 180-fold. The β-arrestin recr

SUBMITTER: Kim HY 

PROVIDER: S-EPMC9820167 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature