Journal Article

Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders

Jeffrey Conn, P., Christopoulos, Arthur, Lindsley, Craig W.

2009

Overview

Key Points Tremendous advances have been made in the discovery of novel ligands for G-protein-coupled receptors (GPCRs) that act at allosteric sites to regulate receptor function. Small molecules can act at allosteric sites to directly activate the receptor (allosteric agonists) or to potentiate (positive allosteric modulators) or inhibit (negative allosteric modulators) responses to traditional GPCR agonists that act at the orthosteric site. Allosteric modulators of GPCRs often provide higher selectivity for individual GPCR subtypes than has been achieved with traditional orthosteric-site ligands. Allosteric ligands can provide novel modes of efficacy that are not possible with orthosteric-site ligands and may provide advantages as therapeutic agents, such as allosteric potentiator and partial antagonist activity. Two allosteric modulators that are not marketed for treatment of human disorders and multiple allosteric modulators are now advancing in discovery and clinical development programmes. Allosteric modulators may lead to novel therapeutic agents for treatment of multiple psychiatric and neurological disorders, including anxiety disorders, schizophrenia and Alzheimer's disease. G protein–coupled receptors (GPCRs) represent one of the most targeted protein families in pharmaceutical research. Traditionally, drug discovery programmes have searched for ligands that act at endogenous orthosteric sites. Here, Conn and colleagues discuss recent advances in the identification of novel GPCR ligands that act at allosteric sites, highlighting their potential in the treatment of psychiatric and neurological disorders. Despite G-protein-coupled receptors (GPCRs) being among the most fruitful targets for marketed drugs, intense discovery efforts for several GPCR subtypes have failed to deliver selective drug candidates. Historically, drug discovery programmes for GPCR ligands have been dominated by efforts to develop agonists and antagonists that act at orthosteric sites for endogenous ligands. However, in recent years, there have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function. These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Allosteric Regulation / Animals / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cancer Research / Care and treatment / Cell receptors / Central nervous system agents / Central nervous system diseases / Central Nervous System Diseases - drug therapy / Dosage and administration / Drug Design / Drug Evaluation, Preclinical / Genetic aspects / Humans / Ligands / Medicinal Chemistry / Molecular Medicine / Pharmacology/Toxicology / Physiological aspects / Receptors, G-Protein-Coupled - antagonists & inhibitors / review-article