Biphenylyl-N-ethylethanamines induce ERK phosphorylation through 5-HT7R-Gs signaling pathway

Biphenylyl-N-ethylethanamines, novel 5-HT₇R agonists synthesized from 4-chloro-3-iodobenaldehyde, activate the Gs signaling pathway. Among derivatives, compounds 4c and 4f showed potent 5-HT₇R agonism, with EC₅₀ values of 89 and 70 nM, respectively, in cAMP assays. Western blot analysis confirmed dose- and time-dependent ERK phosphorylation, with 4c and 4f inducing sustained pERK expression (14.5- and 11.4-fold at 60 min) compared to 5-HT (4.0-fold), indicating prolonged signaling. Compound 4f exhibited acceptable drug-like properties, including minimal CYP inhibition and moderate microsomal stability. These findings highlight the pharmacological potential of 4f as a 5-HT₇R modulator, warranting further in vivo studies to explore its therapeutic applications.