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Current Topics in Medicinal Chemistry
ISSN (Print): 1568-0266
ISSN (Online): 1873-5294
VOLUME: 2
ISSUE: 6
DOI: 10.2174/1568026023393741      Price:  $58









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

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Author(s): Richard B. Westkaemper and Richard A. Glennon
Pages 575-598 (24)
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
Affiliation:
Department of MedicinalChemistry, School of Pharmacy, Virginia Commonwealth University,Richmond, VA 23298 USA