title: Discovery of a new series of centrally active tricyclic isoxazoles combining serotonin (5-HT) reuptake inhibition with alpha2-adrenoceptor blocking activity.
abstract: The synthesis and pharmacology of a new series of 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles that combine central serotonin (5-HT) reuptake inhibition with alpha(2)-adrenoceptor blocking activity is described as potential antidepressants. Four compounds were selected for further evaluation, and the combination of both activities was found to be stereoselective, residing mainly in one enantiomer. Reversal of the loss of righting induced by the alpha(2)-agonist medetomidine in rats confirmed the alpha(2)-adrenoceptor blocking activity in vivo and also demonstrated CNS penetration. Antagonism of p-chloroamphetamine (pCA)-induced excitation as well as blockade of the neuronal 5-HT depletion induced by p-CA administration in rats confirmed their ability to block the central 5-HTT, even after oral administration. Replacement of the oxygen atom at the 5-position of the tricyclic scaffold by a nitrogen or a carbon atom, as well as O-substitution at position 7, led also to active compounds, both in vitro and in vivo.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen-Cilag, Medicinal Chemistry dept., Jarama s/n, 45007 Toledo, Spain. iandres@prdes.jnj.com
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.forename: Jesús
authors.initials: J
authors.lastname: Alcázar
authors.forename: José M
authors.initials: JM
authors.lastname: Alonso
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Alvarez
authors.forename: Margot H
authors.initials: MH
authors.lastname: Bakker
authors.forename: Ilse
authors.initials: I
authors.lastname: Biesmans
authors.forename: José M
authors.initials: JM
authors.lastname: Cid
authors.forename: Ana I
authors.initials: AI
authors.lastname: De Lucas
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández
authors.forename: Luis M
authors.initials: LM
authors.lastname: Font
authors.forename: Koen A
authors.initials: KA
authors.lastname: Hens
authors.forename: Laura
authors.initials: L
authors.lastname: Iturrino
authors.forename: Ilse
authors.initials: I
authors.lastname: Lenaerts
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez
authors.forename: Anton A
authors.initials: AA
authors.lastname: Megens
authors.forename: Joaquín
authors.initials: J
authors.lastname: Pastor
authors.forename: Patrick C M
authors.initials: PC
authors.lastname: Vermote
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
mesh_terms: D000284:Administration, Oral; D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020926:Medetomidine / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000928:Antidepressive Agents; D006575:Heterocyclic Compounds, 3-Ring; D007555:Isoxazoles; D020926:Medetomidine; D011804:Quinolines; D017367:Selective Serotonin Reuptake Inhibitors; D013764:Tetrahydronaphthalenes; C500073:7,8-dimethoxy-3-(4-(2-methyl-3-phenyl-2-propen-1-yl)piperazin-1-ylmethyl)-3,3a,4,5-tetrahydroquinolino(4,3-c)isoxazole