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Research Letter: Structural Combination of Established 5‐HT 2A Receptor Ligands: New Aspects of the Binding Mode
Author(s) -
Kramer Vasko,
Herth Matthias M.,
Santini Martin A.,
Palner Mikael,
Knudsen Gitte M.,
Rösch Frank
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2010.01011.x
Subject(s) - piperidine , moiety , chemistry , steric effects , stereochemistry , receptor , binding site , in vitro , biochemistry
MH.MZ, MDL 100907, and altanserin are structurally similar 4‐benzoyl‐piperidine derivatives and are well accommodated to receptor interaction models. We combined structural elements of different high‐affinity and selective 5‐HT 2A antagonists, as MH.MZ, altanserin, and SR 46349B, to improve the binding properties of new compounds. Three new derivatives were synthesized with a 4‐benzoyl‐piperidine moiety as the lead structure. The in vitro affinity of the novel compounds was determined by a [ 3 H]MDL 100907 competition binding assay. The combination of MH.MZ and SR 46349B resulted in a compound ( 8 ) with a moderate affinity toward the 5‐HT 2A receptor ( K i = 57 n m ). The remarkably reduced affinity of other compounds ( 4a ), ( 4b ), and (4c) ( K i = 411, 360 and 356 n m respectively) indicates that MH.MZ can only bind to the 5‐HT 2A receptor with the p ‐fluorophenylethyl residue in a sterically restricted hydrophobic binding pocket.