We designed and synthesized a new biphenyl amide-tryptamine hybrid molecule <b>7</b> utilizing a pharmacophore-based approach as a 5-HT<sub>2B</sub> antagonist. The hybrid compound <b>7</b> was evaluated for its affinity to a panel of seven 5-HT receptors, demonstrating high selectivity for the 5-HT<sub>2B</sub> receptor. Functional assays revealed potent antagonism of 5-HT<sub>2B</sub> by <b>7</b> with an IC<sub>50</sub> value of 14.1 nM. Moreover, compound <b>7</b> possessed a desirable <i>in vitro</i> 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-HT<sub>2B</sub> antagonists.