Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D(3)-Selective Antagonists

dc.creatorKim, Ho Young
dc.creatorLee, Ji Youn
dc.creatorHsieh, Chia-Ju
dc.creatorTaylor, Michelle
dc.creatorLuedtke, Robert R.
dc.creatorMach, Robert H.
dc.creator.orcid0000-0001-8469-2371 (Luedtke, Robert R.)
dc.date.accessioned2023-02-07T21:55:47Z
dc.date.available2023-02-07T21:55:47Z
dc.date.issued2023-01-09
dc.description.abstractPrevious studies have confirmed that the binding of D(3) receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D(3) receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D(3) receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D(3) receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D(3) receptor affinities (Ki = 0.8-13.2 nM) with subtype selectivity to the D(2) receptor ranging from 22- to 180-fold. The beta-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC(50) = 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 D(3) receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT(3) receptors and TSPO. The results of this study revealed that a new class of selective D(3) receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.
dc.description.sponsorshipThis work was supported by a grant from National Institute on Drug Abuse, grant number DA029840.
dc.identifier.citationKim, H. Y., Lee, J. Y., Hsieh, C. J., Taylor, M., Luedtke, R. R., & Mach, R. H. (2022). Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D3-Selective Antagonists. International journal of molecular sciences, 24(1), 432. https://doi.org/10.3390/ijms24010432
dc.identifier.issn1422-0067
dc.identifier.issue1
dc.identifier.urihttps://hdl.handle.net/20.500.12503/32013
dc.identifier.volume24
dc.publisherMDPI
dc.relation.urihttps://doi.org/10.3390/ijms24010432
dc.rights.holder© 2022 by the authors.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceInternational Journal of Molecular Sciences
dc.subjectD3 receptor antagonists
dc.subjectbitopic ligand
dc.subjectcomputational chemistry
dc.subjectmetoclopramide
dc.subjectbeta-arrestin recruitment assay
dc.subject.meshLigands
dc.subject.meshReceptors, Dopamine D2 / metabolism
dc.subject.meshReceptors, Dopamine D3 / metabolism
dc.subject.meshDopamine
dc.subject.meshStructure-Activity Relationship
dc.subject.meshBenzamides / chemistry
dc.titleDesign and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D(3)-Selective Antagonists
dc.typeArticle
dc.type.materialtext

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