{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kim HY"],"funding":["NIDA NIH HHS","National Institute on Drug Abuse","NIH HHS"],"pagination":["432"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9820167"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["24(1)"],"pubmed_abstract":["Previous studies have confirmed that the binding of D<sub>3</sub> receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D<sub>3</sub> receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D<sub>3</sub> receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D<sub>3</sub> receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D<sub>3</sub> receptor affinities (<i>K</i>i = 0.8-13.2 nM) with subtype selectivity to the D<sub>2</sub> receptor ranging from 22- to 180-fold. The β-arrestin recr"],"journal":["International journal of molecular sciences"],"pubmed_title":["Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D<sub>3</sub>-Selective Antagonists."],"pmcid":["PMC9820167"],"funding_grant_id":["DA029840","S10 OD023495","R01 DA029840"],"pubmed_authors":["Luedtke RR","Mach RH","Kim HY","Hsieh CJ","Lee JY","Taylor M"],"additional_accession":[]},"is_claimable":false,"name":"Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D<sub>3</sub>-Selective Antagonists.","description":"Previous studies have confirmed that the binding of D<sub>3</sub> receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D<sub>3</sub> receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D<sub>3</sub> receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D<sub>3</sub> receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D<sub>3</sub> receptor affinities (<i>K</i>i = 0.8-13.2 nM) with subtype selectivity to the D<sub>2</sub> receptor ranging from 22- to 180-fold. The β-arrestin recr","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2026-04-08T11:13:45.728Z","creation":"2025-02-18T22:34:25.871Z"},"accession":"S-EPMC9820167","cross_references":{"pubmed":["36613875"],"doi":["10.3390/ijms24010432"]}}