title: Synthesis, structure-affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: structural factors contributing to selectivity.
abstract: Histamine H(1) and serotonin 5-HT(2A) receptors present in the CNS have been implicated in various neuropsychiatric disorders. 9-Aminomethyl-9,10-dihydroanthracene (AMDA), a conformationally constrained diarylalkyl amine derivative, has affinity for both of these receptors. A structure-affinity relationship (SAFIR) study was carried out studying the effects of N-methylation, varying the linker chain length and constraint of the aromatic rings on the binding affinities of the compounds with the 5-HT(2A) and H(1) receptors. Homology modeling of the 5-HT(2A) and H(1) receptors suggests that AMDA and its analogs, the parent of which is a 5-HT(2A) antagonist, can bind in a fashion analogous to that of classical H(1) antagonists whose ring systems are oriented toward the fifth and sixth transmembrane helices. The modeled orientation of the ligands are consistent with the reported site-directed mutagenesis data for 5-HT(2A) and H(1) receptors and provide a potential explanation for the selectivity of ligands acting at both receptors.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, PO Box 980540, Richmond, VA 23298, USA.
authors.forename: Jitesh R
authors.initials: JR
authors.lastname: Shah
authors.forename: Philip D
authors.initials: PD
authors.lastname: Mosier
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
authors.forename: Richard B
authors.initials: RB
authors.lastname: Westkaemper
mesh_terms: D000595:Amino Acid Sequence; D000873:Anthracenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry* / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: C122082:9-(aminomethyl)-9,10-dihydroanthracene; D000873:Anthracenes; D044402:Receptor, Serotonin, 5-HT2A; D011969:Receptors, Histamine H1
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