Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

Abstract

Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1–5 and 7 (mGlu 1–57) highlighting key concepts (“molecular switches”, signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.

Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2

“…30 Initial drug discovery efforts focused on non-selective mGlu 2/3 agonists and antagonists that bind to the mGlu orthosteric binding site (evolutionarily conserved glutamate binding site); 31 however, in recent years there has been a shift towards allosteric modulation strategies (consisting of positive and negative allosteric modulators; abbreviated as PAM and NAM, respectively) that offer the potential for improved selectivity for mGlu 2 or mGlu 3 . 32,33 While a wide range of highly selective mGlu 2 PAMs have been discovered and recently reviewed, 33,34 the development of selective mGlu 2 NAMs has remained in its nascent stage with only one report based on a dihydroquinoline 2-carboxamide scaffold in the primary literature. 35 …”

Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

“…On the other hand, highly selective allosteric modulators have been developed for several of the mGlus, 3 with negative allosteric modulators (NAMs) of mGlu 5 representing one of the most advanced areas in this growing field. 4 Potential therapeutic applications for mGlu 5 NAMs are extensive and include many different types of psychiatric and neurodegenerative disorders.…”

Ligand-based virtual screen for the discovery of novel M5 inhibitor chemotypes

“…Two points were considered for modification, namely the oxathiolane spirocycle, analogs 8 (Table 2) and the heterocyclic sulfonamide congeners, 9 (Table 3). SAR was steep, 15–17 with all analogs displaying IC 50 s >10 μM; however, the EC 80 was diminished. The 1,3-oxathiolane ( 4 ) was critical for activity, as the parent piperidinone, 1,3-dithiolane ( 8a ), 1,3-dioxolane ( 8b ) and spiro furan ( 8c ) analogs all showed weak inhibition of M 5 (IC 50 s >10 μM, single point % inhibition at 10 mM form 37–86%).…”

“…Here, employing the standard [ 3 H]-NMS ligand (Figure 4B), 1–3 and compared to atropine, 4 proved to interact with or modulate with orthosteric site with a K i of 2.7 μM (atropine control, K i = 2.7 nM). 1–3,15–17 However, the effect on NMS binding could be due to cooperativity with the orthosteric site by binding of 4 to an allosteric site, or it could reflect direct, competitive interaction at the orthosteric site. Based on 4 being a small, non-basic chemotype, distinct from prototypical mAChR antagonists, and some measure of mAChR selectivity, more potent analogs are required to definitively address the mode of inhibition of M 5 .…”