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Synthesis, structure-affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: structural factors contributing to selectivity. Bioorg Med Chem 2009 Sep 15;17(18):6496-504



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Pubmed Central ID




Scopus ID

2-s2.0-69249122527 (requires institutional sign-in at Scopus site)   20 Citations


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.

Author List

Shah JR, Mosier PD, Roth BL, Kellogg GE, Westkaemper RB


Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Models, Molecular
Molecular Sequence Data
Protein Binding
Protein Conformation
Receptor, Serotonin, 5-HT2A
Receptors, Histamine H1
Sequence Alignment
Structure-Activity Relationship