biostudies-literatureKim HYNIDA NIH HHSNational Institute on Drug AbuseNIH HHS432https://www.ebi.ac.uk/biostudies/studies/S-EPMC9820167biostudies-literatureUnknown24(1)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 (<i>K</i>i = 0.8-13.2 nM) with subtype selectivity to the D₂ receptor ranging from 22- to 180-fold. The β-arrestin recrInternational journal of molecular sciencesDesign and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D₃-Selective Antagonists.PMC9820167DA029840S10 OD023495R01 DA029840Luedtke RRMach RHKim HYHsieh CJLee JYTaylor MfalseDesign 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 (<i>K</i>i = 0.8-13.2 nM) with subtype selectivity to the D₂ receptor ranging from 22- to 180-fold. The β-arrestin recr2022-01-01T00:00:00Z2022 Dec2026-04-08T11:13:45.728Z2025-02-18T22:34:25.871ZS-EPMC98201673661387510.3390/ijms24010432