A series of tris-(phenylalkyl)amines was synthesized and evaluated for affinity to human 5-HT2 receptors. The compounds generally displayed high affinity (4 of 11 analogs had Ki values < 10 nM) and good selectivity for the 5-HT2B receptor over other 5-HT2 subtypes. Functional assays confirmed they act as 5-HT2B antagonists. 5-HT2B antagonists have potential for treating migraine, irritable bowel syndrome, pulmonary hypertension, and heart failure, but no clinically approved agents exist due to selectivity and ADME limitations. This work describes the serendipitous discovery of this new tris-(phenylalkyl)amine scaffold with strong 5-HT2B affinity and selectivity. Its facile synthesis makes it attractive for further structure-activity relationship studies to optimize affinity, selectivity, and antagonist activity in the development of 5-HT2B antagonist therapeutics.