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

Date

2023-01-09

Authors

Kim, Ho Young
Lee, Ji Youn
Hsieh, Chia-Ju
Taylor, Michelle
Luedtke, Robert R.
Mach, Robert H.

ORCID

0000-0001-8469-2371 (Luedtke, Robert R.)

Journal Title

Journal ISSN

Volume Title

Publisher

MDPI

Abstract

Previous 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.

Description

Citation

Kim, 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

Rights

© 2022 by the authors.

License

Attribution 4.0 International (CC BY 4.0)