SAR Studies on mGlu₅ Receptor Positive Allosteric Modulators (2003- 2013)

Title:SAR Studies on mGlu₅ Receptor Positive Allosteric Modulators (2003- 2013)

Volume: 14 Issue: 15

Author(s): Junliang Hao and Hui Xiong

Affiliation:

Keywords: GPCR, mGlu₅ receptor, positive allosteric modulators (PAM), SAR, schizophrenia.

Abstract: 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.

Cite this article as:

Hao Junliang and Xiong Hui, SAR Studies on mGlu₅ Receptor Positive Allosteric Modulators (2003- 2013), Current Topics in Medicinal Chemistry 2014; 14 (15) . https://dx.doi.org/10.2174/1568026614666140826120419