Title:Recent Developments in Group I Metabotropic Glutamate Receptor Allosteric Modulators for the Treatment of Psychiatric and Neurological Disorders (2014-May 2015)
Volume: 16
Issue: 29
Author(s): Guiying Li, Morten Jorgensen, Brian M. Campbell and Dario Doller
Affiliation:
Keywords:
Metabotropic glutamate receptor 1 (mGlu1), Metabotropic glutamate receptor 5 (mGlu5), Negative allosteric modulator
(NAM), Positive allosteric modulator (PAM).
Abstract: In the last ~30 years, scientists have made great strides in understanding the biological
function of group I metabotropic glutamate receptors (mGlu) in health and disease, as well as developing
a broad array of potent and selective agents able to activate or inhibit these receptors. This article
provides a comprehensive review of the most recent group I mGlu modulators published in patent
and non-patent literatures from 2014 to May, 2015, including design, structure-activity relationship,
in silico, in vitro and in vivo properties of key compounds. The current status of clinical mGlu5 negative
allosteric modulators (NAMs) and the development of mGlu1 and mGlu5 PET ligands are also
highlighted. While the therapeutic potential for group I mGlu modulating agents appears high, significant
challenges remain. Strategies to reduce clinical development risks and mitigate important
side effects, including psychotomimetic events observed with several mGlu5 NAMs and cellular toxicity
associated with mGlu5 positive allosteric modulators (PAMs), while retaining therapeutic efficacy
through approaches such as biased ligand signaling are discussed.
