We designed and synthesized a new biphenyl amide–tryptamine hybrid molecule 7 utilizing a pharmacophore-based approach as a 5-HT2B antagonist. The hybrid compound 7 was evaluated for its affinity to a panel of seven 5-HT receptors, demonstrating high selectivity for the 5-HT2B receptor. Functional assays revealed potent antagonism of 5-HT2B by 7 with an IC50 value of 14.1 nM. Moreover, compound 7 possessed a desirable in vitro pharmacokinetic profile and maintained its antagonistic potency in the presence of physiological concentrations of serum proteins. The design approach implemented in this investigation would facilitate the development of a second generation of highly selective and potent 5-HT2B antagonists.
