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).

Small molecule 5-HT_2CR PAMs would not act as an orthosteric agonists (as does lorcaserin), but instead act at distinct allosteric site(s) on the 5-HT_2CR and potentiate signaling of an orthosteric ligand (Fig. 1). The first identified 5-HT_2CR PAM was the fatty acid oleamide [2], which lacked selectivity against other GPCRs. In 2003, chemical library screening resulted in the discovery of an analogue of the antibiotic lincomycin, PNU-69176E, as a selective 5-HT_2CR PAM [3]. In 2012, Zhou and colleagues optimized the synthetic route to generate PNU-69176E and its diastereomer [4], and we have recently designed, synthesized and characterized a series of new chemical entities as selective 5-HT_2CR PAMs [5]. Several molecules potentiated 5-HT_2CR-evoked signaling in vitro without displaying 5-HT_2CR efficacy or altering 5-HT_2AR signaling. CYD-1-79 exhibited a favorable overall pharmacokinetic profile, potentiated 5-HT_2CR-mediated behaviors, and attenuated impulsive action and sensitivity to cocaine-associated cues in a preclinical self-administration model. This series of 5-HT_2CR PAMs is complemented by the discovery of a 5-HT_2CR PAM, which suppressed food intake in rodents [6]. Thus, the chemical space for discovery of novel 5-HT_2CR neuroprobes and therapeutics is now expanding to include allosteric 5-HT_2CR modulators, providing the opportunity to explore cellular mechanisms of action, functional selectivity, neurochemical mechanisms, and neural sites of action for 5-HT_2CR to control behavior.

Fig. 1

The orthosteric and allosteric sites on the 5-HT_2C receptor are distinct. Serotonin binds to the orthosteric site to generate downstream signaling. The 5-HT_2CR PAM CYD-1-79 (cis-4-alkylpiperidine-2-carboxamide series) increases 5-HT efficacy through actions at the allosteric site [5]