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.

Article Details

Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
Clozapine5-hydroxytryptamine receptor 2AKi (nM)9.1N/AN/ADetails
Clozapine5-hydroxytryptamine receptor 2AKi (nM)36N/AN/ADetails
Clozapine5-hydroxytryptamine receptor 2CKi (nM)73N/AN/ADetails
Clozapine5-hydroxytryptamine receptor 2CKi (nM)9.3N/AN/ADetails
Mianserin5-hydroxytryptamine receptor 2AKi (nM)8.1N/AN/ADetails
Mianserin5-hydroxytryptamine receptor 2AKi (nM)27N/AN/ADetails
Mianserin5-hydroxytryptamine receptor 2CKi (nM)8N/AN/ADetails
Mianserin5-hydroxytryptamine receptor 2CKi (nM)1.7N/AN/ADetails