Beyond small-molecule SAR: using the dopamine D3 receptor crystal structure to guide drug design.
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.
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland, USA.
Thomas M
TM
Keck
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland, USA.
Caitlin
C
Burzynski
Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Cornell Medical College, New York, USA.
Lei
L
Shi
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland, USA. Electronic address: anewman@intra.nida.nih.gov.
Amy Hauck
AH
Newman
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D018360:Crystallography, X-Ray; D015259:Dopamine Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D050637:Receptors, Dopamine D3 / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D013329:Structure-Activity Relationship; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000378:metabolism
D015259:Dopamine Agents; D050637:Receptors, Dopamine D3
Addiction; Crystal structure; Pharmacology; Receptor homology modeling; Structure–activity relationships