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

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.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Wood MR,Hopkins CR,Brogan JT,Conn PJ,Lindsley CW

doi

10.1021/bi200129s

subject

Has Abstract

pub_date

2011-04-05 00:00:00

pages

2403-10

issue

13

eissn

0006-2960

issn

1520-4995

journal_volume

50

pub_type

杂志文章,评审

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