title: Application of ligand SAR, receptor modeling and receptor mutagenesis to the discovery and development of a new class of 5-HT(2A) ligands.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA. richard.westkaemper@vcu.edu
authors.forename: Richard B
authors.initials: RB
authors.lastname: Westkaemper
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000873:Anthracenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D016296:Mutagenesis / Q000235:genetics / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D012243:Rhodopsin / Q000737:chemistry / Q000378:metabolism; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C122082:9-(aminomethyl)-9,10-dihydroanthracene; D000873:Anthracenes; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012243:Rhodopsin