title: Synthesis of 3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles, displaying combined 5-HT uptake inhibiting and alpha(2)-adrenoceptor antagonistic activities: a novel series of potential antidepressants.
abstract: The synthesis of a series of novel 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles as novel dual 5-HT reuptake inhibitors and alpha(2)-adrenoceptor antagonists is described. Their affinity at the three different human alpha(2)-adrenoceptor subtypes and the 5-HT transporter site is reported. The in vivo activity of the compounds was measured in two different assays: (1). inhibition of pCA-induced excitation, which evaluates the ability to block the central 5-HT transporter, and (2). inhibition of xylazine-induced loss of righting, which evaluates the ability to block central alpha(2)-adrenoceptors.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Medicinal Chemistry Department, 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: 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: Sonia
authors.initials: S
authors.lastname: Martínez
authors.forename: Carmen
authors.initials: C
authors.lastname: Nieto
authors.forename: Joaquín
authors.initials: J
authors.lastname: Pastor
authors.forename: Margot H
authors.initials: MH
authors.lastname: Bakker
authors.forename: Ilse
authors.initials: I
authors.lastname: Biesmans
authors.forename: Lieve I
authors.initials: LI
authors.lastname: Heylen
authors.forename: Anton A
authors.initials: AA
authors.lastname: Megens
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014991:Xylazine / Q000037:antagonists & inhibitors
chemical_list: D000317:Adrenergic alpha-Antagonists; D000928:Antidepressive Agents; D002352:Carrier Proteins; D007555:Isoxazoles; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014991:Xylazine; C493232:Slc6a4 protein, rat