Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds and (2-methylaminophenoxyethyl and 2-(1-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints" that translated into distinct profiles. , showed biased agonism for ERK1/2 phosphorylation and, , it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment and potently elicited lower lip retraction , a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.