Chemical Biology & Drug Design 2010-10-01

Structural combination of established 5-HT(2A) receptor ligands: new aspects of the binding mode.

Vasko Kramer, Matthias M Herth, Martin A Santini, Mikael Palner, Gitte M Knudsen, Frank Rösch

Index: Chem. Biol. Drug Des. 76(4) , 361-6, (2010)

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Abstract

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 [³H]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 nm). The remarkably reduced affinity of other compounds (4a), (4b), and (4c) (K(i) = 411, 360 and 356 nm 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.© 2010 John Wiley & Sons A/S.