Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders

Abstract

Despite G-protein-coupled receptors (GPCRs) being among the most fruitful targets for marketed drugs, intense discovery efforts for several GPCR subtypes have failed to deliver selective drug candidates. Historically, drug discovery programmes for GPCR ligands have been dominated by efforts to develop agonists and antagonists that act at orthosteric sites for endogenous ligands. However, in recent years, there have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function. These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.

Figure 1. Modes of action of allosteric modulators

a | Allosteric ligands bind to a topographically distinct site on a receptor to modulate orthosteric ligand affinity (red) and/or efficacy (blue). Some allosteric ligands can directly perturb signalling in their own right (green). b | Simulations show the effects on the binding (left) or function (right) of an orthosteric agonist mediated by three different allosteric potentiators: the first (red) enhances orthosteric agonist affinity only; the second (blue) enhances orthosteric agonist efficacy only; the third (green) modestly enhances both affinity and efficacy, and also displays allosteric agonism. Note the potential for differences in observed outcome depending on assay format and that the baseline is 50% specific binding.

Figure 2. Allosteric modulators of gPcr-associated signalling pathways

a | Chemical structures of allosteric modulators known to differentially modulate signalling pathways that are associated with a given G-protein-coupled receptor in a common cellular background. b | Differential effects of the allosteric modulator, N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), on dihydroxyphenylglycol (DHPG)-mediated calcium signalling (left), or extracellular signal regulated kinase (ERK) 1/2 phosphorylation (right) through the endogenous mGluR5 receptor in rat cortical astrocytes. Data from ref. . M, motor; pERK1/2, phosphorylated ERK1/2; tERK1/2, total ERK1/2.

Figure 3. structures of the two marketed gPcr allosteric modulators

Cinacalet (compound 3) is a positive allosteric modulator of the calcium sensing receptor and is used to treat hyperparathyroidism. Maraviroc (compound 4) is a negative allosteric modulator of chemokine receptor 5 that inhibits HIV entry into cells and is used to treat HIV infections.