Synthesis, structure-affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: Structural factors contributing to selectivity

Histamine H-1 and serotonin 5-HT2A 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-HT2A and H-1 receptors. Homology modeling of the 5-HT2A and H-1 receptors suggests that AMDA and its analogs, the parent of which is a 5-HT2A 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-HT2A and H-1 receptors and provide a potential explanation for the selectivity of ligands acting at both receptors. (C) 2009 Published by Elsevier Ltd.