title: Synthesis and SAR of highly potent dual 5-HT1A and 5-HT1B antagonists as potential antidepressant drugs.
abstract: Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT(1A) and 5-HT(1B) receptors. Strategies for the development of dual 5-HT(1A) and 5-HT(1B) antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT(1A) and the 5-HT(1B) receptors and was characterized further with respect to selectivity, electrically stimulated [(3)H]5-HT release and in vivo efficacy.
authors.affiliation: Neuroscience Discovery, Abbott GmbH & Co. KG, D-67008 Ludwigshafen, Germany. andreas.kling@abbott.com
authors.forename: Andreas
authors.initials: A
authors.lastname: Kling
authors.forename: Udo E W
authors.initials: UE
authors.lastname: Lange
authors.forename: Helmut
authors.initials: H
authors.lastname: Mack
authors.forename: Margot H M
authors.initials: MH
authors.lastname: Bakker
authors.forename: Karla U
authors.initials: KU
authors.lastname: Drescher
authors.forename: Wilfried
authors.initials: W
authors.lastname: Hornberger
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hutchins
authors.forename: Achim
authors.initials: A
authors.lastname: Möller
authors.forename: Reinhold
authors.initials: R
authors.lastname: Müller
authors.forename: Martin
authors.initials: M
authors.lastname: Schmidt
authors.forename: Liliane
authors.initials: L
authors.lastname: Unger
authors.forename: Karsten
authors.initials: K
authors.lastname: Wicke
authors.forename: Kurt
authors.initials: K
authors.lastname: Schellhaas
authors.forename: Gerd
authors.initials: G
authors.lastname: Steiner
mesh_terms: D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists; D013329:Structure-Activity Relationship
chemical_list: C433863:5-chloro-2,3-dihydro-6-(4-methylpiperazin-1-yl)-1-(4-(pyridin-4-yl)naphth-1-ylaminocarbonyl)-1H-indole; D000928:Antidepressive Agents; D007211:Indoles; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists