Positive-allosteric modulation of the 5-HT_2C receptor: implications for neuropsychopharmacology and neurotherapeutics

Serotonin (5-hydroxytryptamine; 5-HT) was identified in the mammalian brain in the 1950s. We now recognize brain 5-HT to actualize flexible and complex actions directed by binding to at least 14 5-HT receptors as well as the serotonin reuptake transporter. The 5-HT_2C receptor (5-HT_2CR) is a G protein-coupled receptor (GPCR) that has been implicated in psychiatric and neurological disorders, including anxiety, depression, schizophrenia, and substance use disorders as well as obesity. The orthosteric 5-HT_2CR site, at which the endogenous agonist binds, has been a primary target for ligand discovery for obesity based upon the role of 5-HT_2CR in the control of feeding, energy and glucose homeostasis, yielding the first-in-class 5-HT_2CR agonist lorcaserin (Belviq^®) approved by the FDA for weight loss. While 5-HT_2CR antagonism potentially mediates the side effect of some antipsychotics (e.g., clozapine) to increase weight gain, the development of 5-HT_2CR antagonists has been pursued for the treatment of anxiety disorders and depression. Importantly, selective agonists and antagonists have advanced knowledge of 5-HT_2CR neuropsychopharmacology.

Binding of 5-HT to the 5-HT_2CR results in a conformational change that catalyzes the diffusion of multiple second messenger effectors and G protein-dependent signaling. An allosteric modulator is a ligand that binds to a spatially distinct allosteric site(s) and alters the receptor conformation to modulate its interaction with other ligands and/or signal transduction molecules [1]. Higher sequence divergence for allosteric sites is expected across receptor subtypes relative to the highly conserved orthosteric domain. Such allosteric modulation is saturable (comes to a finite magnitude when the allosteric site is fully occupied) and probe-dependent (varies dependent upon the orthosteric ligand) with the prospects for separate control of affinity and efficacy. A positive- (PAM) or negative-allosteric modulator (NAM) can enhance or inhibit the functional response to an orthosteric agonist, while silent allosteric ligands are suggested to compete with PAMs or NAMs at the allosteric binding site. Additionally, allosteric ligands can be antagonists or agonists with, or without, PAM or NAM activity (e.g., ago-PAMs, ligands that potentiate agonists and display intrinsic efficacy).

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