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.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Shah JR,Mosier PD,Roth BL,Kellogg GE,Westkaemper RBdoi
10.1016/j.bmc.2009.08.016subject
Has Abstractpub_date
2009-09-15 00:00:00pages
6496-504issue
18eissn
0968-0896issn
1464-3391pii
S0968-0896(09)00768-8journal_volume
17pub_type
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