title: Design, synthesis, and pharmacological characterization of N- and O-substituted 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol analogues: novel 5-HT(2A)/5-HT(2C) receptor agonists with pro-cognitive properties.
abstract: The isoxazol-3-one tautomer of the bicyclic isoxazole, 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol (THAZ), has previously been shown to be a weak GABA(A) and glycine receptor antagonist. In the present study, the potential in this scaffold has been explored through the synthesis and pharmacological characterization of a series of N- and O-substituted THAZ analogues. The analogues N-Bn-THAZ (3d) and O-Bn-THAZ (4d) were found to be potent agonists of the human 5-HT(2A) and 5-HT(2C) receptors. Judging from an elaborate pharmacological profiling at numerous other CNS targets, the 3d analogue appears to be selective for the two receptors. Administration of 3d substantially improved the cognitive performance of mice in a place recognition Y-maze model, an effect fully reversible by coadministration of the selective 5-HT(2C) antagonist SB242084. In conclusion, as novel bioavailable cognitive enhancers that most likely mediate their effects through 5-HT(2A) and/or 5-HT(2C) receptors, the isoxazoles 3d and 4d constitute interesting leads for further medicinal chemistry development.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark. aaj@sund.ku.dk
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.forename: Niels
authors.initials: N
authors.lastname: Plath
authors.forename: Martin H F
authors.initials: MH
authors.lastname: Pedersen
authors.forename: Vignir
authors.initials: V
authors.lastname: Isberg
authors.forename: Jacob
authors.initials: J
authors.lastname: Krall
authors.forename: Petrine
authors.initials: P
authors.lastname: Wellendorph
authors.forename: Tine B
authors.initials: TB
authors.lastname: Stensbøl
authors.forename: David E
authors.initials: DE
authors.lastname: Gloriam
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
mesh_terms: D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001682:Biological Availability; D003071:Cognition / Q000187:drug effects*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001381:Azepines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017366:Serotonin Receptor Agonists