"Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology

Michael R. Wood, Corey R. Hopkins, John T. Brogan, P. Jeffrey Conn, Craig W. Lindsley

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

G-Protein-coupled receptors (GPCRs) represent the largest class of drug targets, accounting for more than 40% of marketed drugs; however, discovery efforts for many GPCRs have failed to provide viable drug candidates. Historically, drug discovery efforts have focused on developing ligands that act at the orthosteric site of the endogenous agonist. Recently, efforts have focused on functional assay paradigms and the discovery of ligands that act at allosteric sites to modulate receptor function in either a positive, negative, or neutral manner. Allosteric modulators have numerous advantages over orthosteric ligands, including high subtype selectivity; the ability to mimic physiological conditions; the lack of densensitization, downregulation, and internalization; and reduced side effects. Despite these virtues, challenging issues have now arisen for allosteric modulators of metabotropic glutamate receptors (mGluRs): shallow SAR, ligand-directed trafficking, and the identification of subtle "molecular switches" that modulate the modes of pharmacology. Here, we will discuss the impact of modest structural changes to multiple mGluR allosteric ligands scaffolds that unexpectedly modulate pharmacology and raise concerns over metabolism and the pharmacology of metabolites.

Original languageEnglish (US)
Pages (from-to)2403-2410
Number of pages8
JournalBiochemistry
Volume50
Issue number13
DOIs
StatePublished - Apr 5 2011

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Switches
Pharmacology
Ligands
G-Protein-Coupled Receptors
Modulators
Pharmaceutical Preparations
Allosteric Site
Metabotropic Glutamate Receptors
Aptitude
Drug Discovery
Metabolites
Metabolism
Scaffolds
Assays
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry

Cite this

"Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology. / Wood, Michael R.; Hopkins, Corey R.; Brogan, John T.; Conn, P. Jeffrey; Lindsley, Craig W.

In: Biochemistry, Vol. 50, No. 13, 05.04.2011, p. 2403-2410.

Research output: Contribution to journalArticle

Wood, Michael R. ; Hopkins, Corey R. ; Brogan, John T. ; Conn, P. Jeffrey ; Lindsley, Craig W. / "Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology. In: Biochemistry. 2011 ; Vol. 50, No. 13. pp. 2403-2410.
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