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-HT2A 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-HT2A receptor (Ki = 57 nm). The remarkably reduced affinity of other compounds (4a), (4b), and (4c) (Ki = 411, 360 and 356 nm respectively) indicates that MH.MZ can only bind to the 5-HT2A receptor with the p-fluorophenylethyl residue in a sterically restricted hydrophobic binding pocket.