Translating biased agonists from molecules to medications: Serotonin 5-HT_1A receptor functional selectivity for CNS...

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-HT_1A receptors, which exert a major 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-HT_1A receptors, whereas NLX-112 (a.k.a. befiradol or F13640) shows prominent activation of 5-HT_1A 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 ¹⁸F to produce the first agonist PET radiopharmaceutical (known as [¹⁸F]-F13640) for investigation of the active state of 5-HT_1A 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-HT_1A receptors and new profiles of cellular signaling bias, notably for β-arrestin recruitment versus pERK. Taken together, the data suggest that 5-HT_1A receptor biased agonists constitute potentially superior pharmacological agents for treatment of CNS disorders involving serotonergic mechanisms.