The present review describes our approach to the development of a structurally unique class of 5-HT(2A) ligands. On the basis of an abbreviated graphics model of a 5-HT(2A) serotonin receptor, it was hypothesized that introduction of an additional aromatic ring might enhance the affinity of phenylethylamine (an agent that lacks significant affinity for the 5-HT(2A) receptors). Continued work with such structures, and the continual refinement of graphics receptor models, ultimately led to the identification of AMDA (27, 5-HT(2A) K(i) = 20 nM). AMDA is a 5-HT(2A) antagonist that, unlike certain other tricyclic 5-HT(2A) antagonists, binds with very low affinity at dopamine D(2) receptors, the serotonin transporter, and the norepinephrine transporter. Comparative structure-affinity studies indicate that AMDA binds in a manner distinct from the tricyclic antagonists Graphics models were employed to identify possible modes of binding. This investigation illustrates the impact of a combination of classical medicinal chemistry, receptor modeling, and molecular biology on novel drug design.