G-Protein-coupled receptors (GPCRs) represent the largest class of drug  targets, accounting for over 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, lack of  densensitization/down regulation/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  (from PAM to NAM or SAM), as well as mGluR subtype selectivity.   Here,  we will discuss the impact of modest structural changes to multiple  mGluR allosteric ligands scaffolds that unexpectedly modulate  pharmacology and/or subtype selectivity, as well as a concept of  'molecular locks', to describe series free from 'molecular switches'   .    Finally, this talk will convey lessons learned, and raise concerns over  metabolism and the pharmacology of metabolites.

Molecular switches on mGluR allosteric ligands that modulate modes of pharmacology and/or subtype selectivity

243rd National Meeting (2012)

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