Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders

Abstract

Novel allosteric modulators of G protein-coupled receptors (GPCRs) are providing fundamental advances in the development of GPCR ligands with high subtype selectivity and novel modes of efficacy that have not been possible with traditional approaches. As new allosteric modulators are advancing as drug candidates, we are developing an increased understanding of the major advantages and broad range of activities that can be achieved with these agents through selective modulation of specific signalling pathways, differential effects on GPCR homodimers versus heterodimers, and other properties. This understanding creates exciting opportunities, as well as unique challenges, in the optimization of novel therapeutic agents for disorders of the central nervous system.

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

“…It is also suggested that many of the mechanisms underlying allostery, as first formalized in the classic MonodWyman-Changeux (Monod et al, 1965) and Koshland-NemethyFilmer models (Koshland et al, 1966), are likely applicable to other protein classes, including GPCRs (Canals et al, 2011). Advantages of targeting allosteric GPCR sites include the potential for receptor subtype selectivity, either due to greater sequence divergence in allosteric pockets between receptor subtypes relative to the (necessarily) conserved orthosteric site, or due to subtype-selective cooperativity; the ability to fine tune physiologic responses in either a positive or negative direction; and a saturability, or "ceiling," to the effect that may lead to greater on-target safety in overdose situations (May et al, 2007;Christopoulos, 2014;Conn et al, 2014). Allosteric modulators can also display distinct pharmacological properties, including the phenomena of "probe dependence" and "biased agonism/ modulation."…”

Allosteric Binding Site and Activation Mechanism of Class C G-Protein Coupled Receptors: Metabotropic Glutamate Receptor Family

“…Allosteric modulators of mGluRs for treating human CNS disorders are new approaches for the development of therapeutic targets. Lately, several allosteric modulators entered clinical development (8). mGluR5 NAMs have been demonstrated promising effects of in fragile X syndrome, Parkinson's disease, anxiety, and affective disorder in the Phase II clinical trials (21,22).…”

Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia

“…Emerging data on stimulus bias within allosteric GPCR signaling, however, may offer an approach to potentially mitigate these undesired effects that reduce the therapeutic window and preclude development. 11,12 In this Letter, we detail a unique industrial−academic collaboration between Janssen Research and Development and the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) 13 that led to the discovery of a potent, selective, and orally bioavailable mGlu 5 PAM clinical candidate 17a that displays robust antipsychotic and cognition-enhancing efficacy in the absence (stimulus bias) of direct potentiation of NMDA receptor modulation. This is the first disclosure of the SAR and preclinical candidate profile of 17a.…”