Translating biased agonists from molecules to medications: Serotonin 5-HT1A receptor functional selectivity for CNS disorders

Biased agonism(or functional selectivity) at G-protein-coupled receptors has attracted rapidly increasing interest as a means to improve discovery of more efficacious and safer pharmacotherapeutics. However, most studies are limited to in vitro tests of cellular signaling and few biased agonists have progressed to in vivo testing. As concerns 5-HT1A receptors, which exert amajor control of serotonergic signaling in diverse CNS regions, study of biased agonism has previously been limited by the poor target selectivity and/or partial agonism of classically available ligands. However, a new generation of highly selective, efficacious and druggable agonists has advanced the study of biased agonism at this receptor and created new therapeutic opportunities. These novel agonists show differential properties for G-protein signaling, cellular signaling (particularly pERK), electrophysiological effects, neurotransmitter release, neuroimaging by PET and pharmacoMRI, and behavioral tests of mood, motor activity and side effects. Overall, NLX-101 (a.k.a. F15599) exhibits preferential activation of cortical and brain stem 5-HT1A receptors, whereas NLX-112 (a.k.a. befiradol or F13640) shows prominent activation of 5-HT1A autoreceptors in Raphe nuclei and in regions associated with motor control. Accordingly, NLX-101 is potently active in rodent models of depression and respiratory control, whereas NLX-112 shows promising activity in models of Parkinson's disease across several species - rat, marmoset and macaque. Moreover, NLX-112 has also been labeled with F-18 to produce the first agonist PET radiopharmaceutical (known as [F-18]-F13640) for investigation of the active state of 5-HT1A receptors in rodent, primate and human. The structure-functional activity relationships of biased agonists have been investigated by receptor modeling and novel compounds have been identified which exhibit increased affinity at 5-HT1A receptors and newprofiles of cellular signaling bias, notably for beta-arrestin recruitment versus pERK. Taken together, the data suggest that 5-HT1A receptor biased agonists constitute potentially superior pharmacological agents for treatment of CNS disorders involving serotonergic mechanisms. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

Biased agonism at G-protein-coupled receptors has gained increasing interest for the discovery of more effective and safer drugs. However, most studies are limited to in vitro tests, and few biased agonists have been tested in vivo. The study of biased agonism at 5-HT1A receptors has been limited by the availability of ligands with poor target selectivity or partial agonism. However, the development of new selective and efficacious agonists has advanced the study of biased agonism at this receptor and opened up new therapeutic opportunities.