title: 1-(1-phenethylpiperidin-4-yl)-1-phenylethanols as potent and highly selective 5-HT2A antagonists.
abstract: The discovery of a novel class of highly potent and selective 5-HT2A antagonists is reported herein. Selectivity for the serotonin 5-HT2A receptor was optimized, decreasing the affinity of these antagonists toward the adrenergic alpha1 and dopaminergic D2 receptors, and especially to the 5-HT2C receptor. A series of corresponding 7-substituted indoles is described for the first time as serotonergic ligands. The enantiomer R-(+)-1-(4-fluorophenyl)-1-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl} ethanol (R-(+)-74) was identified to have superior affinity for the serotonergic 5-HT2A receptor [IC50=0.37 nM] and selectivity toward the dopaminergic D2- [IC50=2300 nM], adrenergic alpha1- [IC50=1000 nM] and 5-HT2C receptors [IC50=490 nM].
authors.affiliation: Merck KGaA, Preclinical Pharmaceutical Research, Frankfurter Strasse 250, 64293 Darmstadt, Germany. timo.heinrich@merck.de
authors.forename: Timo
authors.initials: T
authors.lastname: Heinrich
authors.forename: Henning
authors.initials: H
authors.lastname: Böttcher
authors.forename: Helmut
authors.initials: H
authors.lastname: Prücher
authors.forename: Rudolf
authors.initials: R
authors.lastname: Gottschlich
authors.forename: Karl-August
authors.initials: KA
authors.lastname: Ackermann
authors.forename: Christoph
authors.initials: C
authors.lastname: van Amsterdam
mesh_terms: D000818:Animals; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists