Metabotropic glutamate receptor 5 (mGlu5) is a class C G-protein-coupled receptor which possesses a large extracellular
N-terminal domain (ATD) connected to the seven-transmembrane (7-TM) domain. In contrast to the glutamate
and its close analogs binding at the orthosteric site on the ATD region, allosteric modulators bind at topographically distinct
sites in the 7-TM region. Activation of mGlu5 receptors at either the orthosteric or allosteric sites results in enhancement
of NMDA receptor function and represents a promising opportunity for the treatment of schizophrenia. Since the
disclosure of the first mGlu5 positive allosteric modulators (PAM) in 2003, there have been intense industry-wide efforts
to discover and develop safe and efficacious agents capable of selectively enhancing mGlu5 receptor function at the allosteric
sites. Over the past decade, tremendous progress has been made, and multiple chemical scaffolds have been identified
as mGlu5 PAMs, possibly binding to different allosteric sites on the 7-TM domain. These ligands have helped gain
novel insights into the biology of mGlu5 receptor allosteric activation. Here we provide a comprehensive review on the
structure-activity relationship (SAR) progress on the mGlu5 PAMs reported in the primary literature and include appropriate
and complementary examples from the patent literature. Important in vivo studies of select compounds from individual
scaffolds are highlighted, and challenges facing the clinical development of mGlu5 receptor PAMs are discussed.
Keywords: GPCR, mGlu5 receptor, positive allosteric modulators (PAM), SAR, schizophrenia.
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