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

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.