Synthesis of Bitopic Ligands Based on Fallypride and Evaluation of Their Affinity and Selectivity Towards Dopamine D and D Receptors

Overview

Journal Eur J Med Chem

Specialty Chemistry

Date 2023 Sep 9

PMID 37688938

Authors

Gui-Long Tian

Chia-Ju Hsieh

Michelle Taylor

Ji Youn Lee

Aladdin A Riad

Robert R Luedtke

Robert H Mach

Affiliations

Soon will be listed here.

Abstract

The difference in the secondary binding site (SBS) between the dopamine 2 receptor (DR) and dopamine 3 receptor (DR) has been used in the design of compounds displaying selectivity for the DR versus DR. In the current study, a series of bitopic ligands based on Fallypride were prepared with various secondary binding fragments (SBFs) as a means of improving the selectivity of this benzamide analog for DR versus DR. We observed that compounds having a small alkyl group with a heteroatom led to an improvement in DR versus DR selectivity. Increasing the steric bulk in the SBF increase the distance between the pyrrolidine N and Asp110, thereby reducing DR affinity. The best-in-series compound was (2S,4R)-trans-27 which had a modest selectivity for DR versus DR and a high potency in the β-arrestin competition assay which provides a measure of the ability of the compound to compete with endogenous dopamine for binding to the DR. The results of this study identified factors one should consider when designing bitopic ligands based on Fallypride displaying an improved affinity for DR versus DR.

Citing Articles

Design and Synthesis of DR Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies.

Tian G, Hsieh C, Taylor M, Lee J, Luedtke R, Mach R Molecules. 2024; 29(1).

PMID: 38202706 PMC: 10779535. DOI: 10.3390/molecules29010123.

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