The present review describes our approach to the development of a structurally unique class of 5- HT2A ligands. On the basis of an abbreviated graphics model of a 5-HT2A 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-HT2A receptors). Continued work with such structures, and the continual refinement of graphics receptor models, ultimately led to the identification of AMDA (27, 5-HT2A Ki = 20 nM). AMDA is a 5-HT2A antagonist that, unlike certain other tricyclic 5-HT2A antagonists, binds with very low affinity at dopamine D2 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.
Receptor Mutagenesis, Pharmacophore Models, Tricyclic Ring System, AMDA Analogs, aminomethyl rotation
Department of MedicinalChemistry, School of Pharmacy, Virginia Commonwealth University,Richmond, VA 23298 USA