title: Structural combination of established 5-HT(2A) receptor ligands: new aspects of the binding mode.
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.
authors.forename: Vasko
authors.initials: V
authors.lastname: Kramer
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Herth
authors.forename: Martin A
authors.initials: MA
authors.lastname: Santini
authors.forename: Mikael
authors.initials: M
authors.lastname: Palner
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
authors.forename: Frank
authors.initials: F
authors.lastname: Rösch
mesh_terms: D001667:Binding, Competitive; D020650:Combinatorial Chemistry Techniques; D005464:Fluorobenzenes / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D007650:Ketanserin / Q000031:analogs & derivatives / Q000737:chemistry; D008024:Ligands; D010636:Phenols / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry* / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000737:chemistry*
chemical_list: D005464:Fluorobenzenes; D008024:Ligands; D010636:Phenols; D010880:Piperidines; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; C076033:SR 46349B; C071983:altanserin; C066738:4-benzoylpyridine; D007650:Ketanserin; C079049:volinanserin