Beyond small-molecule sar: Using the dopamine d3 receptor crystal structure to guide drug design

Thomas M. Keck, Caitlin Burzynski, Lei Shi, Amy Hauck Newman

Research output: Chapter in Book/Report/Conference proceedingChapter

33 Scopus citations

Abstract

The dopamine D3 receptor is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, restless leg syndrome, and drug addiction. The high protein sequence homology between the D3 and D2 receptors has posed a challenge to developing D3 receptor-selective ligands whose behavioral actions can be attributed to D3 receptor engagement, in vivo. However, through primarily small-molecule structure-activity relationship (SAR) studies, a variety of chemical scaffolds have been discovered over the past two decades that have resulted in several D3 receptor-selective ligands with high affinity and in vivo activity. Nevertheless, viable clinical candidates remain limited. The recent determination of the high-resolution crystal structure of the D3 receptor has invigorated structure-based drug design, providing refinements to the molecular dynamic models and testable predictions about receptor-ligand interactions. This chapter will highlight recent preclinical and clinical studies demonstrating potential utility of D3 receptor-selective ligands in the treatment of addiction. In addition, new structure-based rational drug design strategies for D3 receptor-selective ligands that complement traditional small-molecule SAR to improve the selectivity and directed efficacy profiles are examined.

Original languageEnglish (US)
Title of host publicationAdvances in Pharmacology
PublisherAcademic Press Inc.
Pages267-300
Number of pages34
DOIs
StatePublished - 2014

Publication series

NameAdvances in Pharmacology
Volume69
ISSN (Print)1054-3589
ISSN (Electronic)1557-8925

All Science Journal Classification (ASJC) codes

  • Pharmacology

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