Application of Ligand SAR, Receptor Modeling and Receptor Mutagenesis to the Discovery and Development of a New class of 5-HT2A Ligands

Authors: Westkaemper, R.B.; Glennon, R.A.

Source: Current Topics in Medicinal Chemistry, Volume 2, Number 6, 1 June 2002 , pp. 575-598(24)

Publisher: Bentham Science Publishers

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Abstract:

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.

Keywords: Receptor Mutagenesis; Pharmacophore Models; Tricyclic Ring System; AMDA Analogs; aminomethyl rotation

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1568026023393741

Publication date: 2002-06-01