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 recruitment assay revealed that?21c?with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC50?= 1.3 nM). Computational studies demonstrated that the high potency of?21c?and its analogs was the result of interactions with the secondary binding site of the D3?receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT3?receptors and TSPO. The results of this study revealed that a new class of selective D3?receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.
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