Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT <sub>1A</sub> Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile
Joanna Śniecikowska, Monika Głuch‐Lutwin, Adam Bucki, Anna Więckowska, Agata Siwek, Magdalena Jastrzębska‐Więsek, Anna Partyka, Daria Wilczyńska, Karolina Pytka, Gniewomir Latacz, Katarzyna Przejczowska‐Pomierny, Elżbieta Wyska, Anna Wesołowska, Maciej Pawłowski, Adrian Newman‐Tancredi, Marcin Kołaczkowski
Abstract
High Resolution Image Download MS PowerPoint Slide Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT 1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1 H -indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential “signaling fingerprints” that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of “serotonergic syndrome”. Both compounds showed promising developability properties. The presented 5-HT 1A 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.