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.
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Jensen AA, Plath N, Pedersen MH, Isberg V, Krall J, Wellendorph P, Stensbol TB, Gloriam DE, Krogsgaard-Larsen P, Frolund B
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.
J Med Chem. 2013 Feb 14;56(3):1211-27. doi: 10.1021/jm301656h. Epub 2013 Jan 17.
- PubMed ID
- 23301527 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Clozapine 5-hydroxytryptamine receptor 2A Ki (nM) 9.1 N/A N/A Details Clozapine 5-hydroxytryptamine receptor 2A Ki (nM) 36 N/A N/A Details Clozapine 5-hydroxytryptamine receptor 2C Ki (nM) 73 N/A N/A Details Clozapine 5-hydroxytryptamine receptor 2C Ki (nM) 9.3 N/A N/A Details Mianserin 5-hydroxytryptamine receptor 2A Ki (nM) 8.1 N/A N/A Details Mianserin 5-hydroxytryptamine receptor 2A Ki (nM) 27 N/A N/A Details Mianserin 5-hydroxytryptamine receptor 2C Ki (nM) 8 N/A N/A Details Mianserin 5-hydroxytryptamine receptor 2C Ki (nM) 1.7 N/A N/A Details