Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D Receptor

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2016 Dec 17

PMID 27983845

Citations 38

Authors

Mayako Michino

Comfort A Boateng

Prashant Donthamsetti

Hideaki Yano

Oluyomi M Bakare

Alessandro Bonifazi

Michael P Ellenberger

Thomas M Keck

Vivek Kumar

Clare Zhu

Ravi Verma

Jeffrey R Deschamps

Jonathan A Javitch

Amy Hauck Newman

Lei Shi

Affiliations

Soon will be listed here.

Abstract

Both dopamine D receptor (DR) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists, whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of DR in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (S)-enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles.

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