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-HT2A/5-HT2C Receptor Agonists with Pro-Cognitive Properties

Anders A. Jensen, Niels Plath, Martin Holst Friborg Pedersen, Vignir Isberg, Jacob Krall, Petrine Wellendorph, Tine B. Stensbøl, David E. Gloriam, Povl Krogsgaard-Larsen, Bente Frølund

    Research output: Contribution to journalJournal articleResearchpeer-review

    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 GABAA 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-HT2A and 5-HT2C 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-HT2C antagonist SB242084. In conclusion, as novel bioavailable cognitive enhancers that most likely mediate their effects through 5-HT2A and/or 5-HT2C receptors, the isoxazoles 3d and 4d constitute interesting leads for further medicinal chemistry development.
    Original languageEnglish
    JournalJournal of Medicinal Chemistry
    Volume56
    Issue number3
    Pages (from-to)1211-1227
    ISSN0022-2623
    DOIs
    Publication statusPublished - 2013

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