详细信息    查看全文

• 作者：Anders A. Jensen ; Niels Plath ; Martin H. F. Pedersen ; Vignir Isberg ; Jacob Krall ; Petrine Wellendorph ; Tine B. Stensb酶l ; David E. Gloriam ; Povl Krogsgaard-Larsen ; Bente Fr酶lund
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：1211-1227
• 全文大小：698K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

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.