Development of allosteric modulators of GPCRs for treatment of CNS disorders

Abstract

The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than do orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as “bitopic” ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction.

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

“…These selective mGlu 5 NAMs have shown exciting efficacy across preclinical models (Emmitte, 2011;Christopoulos, 2014;Nickols and Conn, 2014) and in clinical development for the treatment of multiple CNS disorders (Berg et al, 2011;Jacquemont et al, 2011;Nickols and Conn, 2014;Lindemann et al, 2015).…”

Evidence for Classical Cholinergic Toxicity Associated with Selective Activation of M1 Muscarinic Receptors

“…This hypothesis has been borne out empirically. For example, small molecules targeting allosteric sites of metabotropic glutamate receptors have been shown to exhibit excellent receptor subtype selectivity, which had not been achieved by ligands targeting the highly conserved glutamate binding site (Nickols and Conn 2014). Similarly, allosteric modulators of muscarinic receptors have been identified that exhibit selectivity superior to that attained by xanomeline or other orthosteric site M 1 receptor activators (Melancon et al, 2013).…”

Location-Dependent Signaling of the Group 1 Metabotropic Glutamate Receptor mGlu5

“…The crystal structure of the seven-transmembrane region of the human mGlu5 receptor bound to the negative allosteric modulator (NAM) mavoglurant (AQ056 [methyl (3aR,4S,7aR)-4-hydroxy-4-[(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate]; Novartis, Basel, Switzerland) was recently resolved (Doré et al, 2014). Together with a similar study that resolved the structure of mGlu1 receptors with the NAM, FITM [4-fluoro-N-(4-(6-(isopropylamino)pyrimidin-4-yl)thiazol-2-yl)-N-methylbenzamide] (Wu et al, 2014), important advances were made in the ability to design selective mGlu receptor modulators targeting the allosteric binding sites (Nickols and Conn, 2014).…”