Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 2 (mGluR2)

Abstract

This article describes recent medicinal chemistry progress toward selective potentiators of the metabotropic glutamate receptor 2 (mGluR2). Groups at Lilly and Merck have identified new classes of potentiators that exhibit selectivity for mGluR2 over the seven other subtypes of mGluRs. Structure-activity relationships as well as pharmacokinetic properties and in vivo activity are reviewed.

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of 11C-JNJ-42491293, A Novel Radioligand for mGluR2

“…Several orthosteric agonists for mGluR2 have been identified and have shown beneficial effects in preclinical behavioral models and in clinical conditions including schizophrenia (2), anxiety (4), and addiction (12) but show narrow therapeutic margins. mGluR2 PAMs are potentially more selective and give a more nuanced approach to enhancing mGluR2 function (13).…”

Drugability of Extracellular Targets: Discovery of Small Molecule Drugs Targeting Allosteric, Functional, and Subunit-Selective Sites on GPCRs and Ion Channels

“…Furthermore the conformational regulation inherent in signal transduction by the endogenous ligand can be coopted in allosteric regulation by pharmacological agents (Niswender et al, 2005;Pin et al, 2005). The TMD has been exploited as a drugable allosteric site for class C GPCRs, especially metabotropic glutamate receptors (Rudd and McCauley, 2005). This domain is tractable for drug development presumably because the membranespanning a-helices are arranged to form a pocket that can bind small molecules, like monoamine receptors.…”

“…Examples of these compounds include cinacalcet (compound 1, Figure 4a), an allosteric enhancer of the calcium-sensing receptor used to treat hypercalcemia associated with renal failure (Harrington and Fotsch, 2007), LY487379 (compound 2, Figure 4a) and other allosteric enhancers of group II mGlu receptors developed as potential treatments for schizophrenia (Rudd and McCauley, 2005), and CGP7930 (compound 3, Figure 4a) along with other GABA B receptor potentiators for treating addiction (Adams and Lawrence, 2007). The structural complexity that has led us down the path of allosteric modulation may also provide therapeutic value.…”

“…As the drug does not activate the calcium-sensing receptor alone, it does not lower blood calcium to dangerous levels thus providing the beneficial effect with limited risk. Allosteric modulation may also aid development of compounds that target specific receptor subtypes that all bind the same endogenous ligand, especially for specific subtypes of the family of eight metabotropic glutamate receptors (Rudd and McCauley, 2005). The endogenous ligand-binding site must preserve some structural similarity through evolution of receptor subtypes to bind the same endogenous ligand (the glutamate-binding domain on the VFT of mGlu receptors) whereas no such evolutionary pressure exists to preserve the structure of novel drugable sites (such as the discrete areas within the TMD).…”

Neuroimaging - Clinical Applications

“…Such compounds are needed to further investigate mGluR function, and as potential therapeutic agents for a variety of neurological diseases, which are associated with the abnormal activation of mGluRs. A large amount of pharmacological agents acting at metabotropic glutamate receptors have been described in the literature (Guitart & Khurdayan, 2005;Kew, 2004;Layton, 2005;Marino et al, 2005;Rudd & McCauley, 2005;Schoepp et al, 1999;Slassi et al, 2005;Williams & Lindsley, 2005;Yang, 2005). According to the mode of binding, these mGluR pharmacological agents can be classified into competitive and non-competitive agents.…”