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

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

doi:10.1021/jm301656h

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

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

43 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	56
Udgave nummer	3
Sider (fra-til)	1211-27
Antal sider	17
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm301656h
Status	Udgivet - 14 feb. 2013

Adgang til dokumentet

10.1021/jm301656h

Fingeraftryk

Dyk ned i forskningsemnerne om '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'. Sammen danner de et unikt fingeraftryk.

Citationsformater

Jensen, A. A., Plath, N., Pedersen, M. H. F., Isberg, V., Krall, J., Wellendorph, P., Stensbøl, T. B., Gloriam, D. E., Krogsgaard-Larsen, P., & Frølund, B. (2013). 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. Journal of Medicinal Chemistry, 56(3), 1211-27. https://doi.org/10.1021/jm301656h

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. / Jensen, Anders A; Plath, Niels; Pedersen, Martin H. F. et al.
I: Journal of Medicinal Chemistry, Bind 56, Nr. 3, 14.02.2013, s. 1211-27.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Jensen, AA, Plath, N, Pedersen, MHF, Isberg, V, Krall, J, Wellendorph, P, Stensbøl, TB, Gloriam, DE , Krogsgaard-Larsen, P & Frølund, B 2013, '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', Journal of Medicinal Chemistry, bind 56, nr. 3, s. 1211-27. https://doi.org/10.1021/jm301656h

Jensen AA, Plath N, Pedersen MHF, Isberg V, Krall J, Wellendorph P et al. 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. Journal of Medicinal Chemistry. 2013 feb. 14;56(3):1211-27. doi: 10.1021/jm301656h

@article{45942c82bbb847cab6da9855638e3784,

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.",

keywords = "Azepines, Biological Availability, Cognition, Drug Design, HEK293 Cells, Humans, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2C, Serotonin Receptor Agonists",

author = "Jensen, {Anders A} and Niels Plath and Pedersen, {Martin H. F.} and Vignir Isberg and Jacob Krall and Petrine Wellendorph and Stensb{\o}l, {Tine B.} and Gloriam, {David E.} and Povl Krogsgaard-Larsen and Bente Fr{\o}lund",

year = "2013",

month = feb,

day = "14",

doi = "10.1021/jm301656h",

language = "English",

volume = "56",

pages = "1211--27",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "3",

}

TY - JOUR

T1 - Design, synthesis, and pharmacological characterization of N- and O-substituted 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol analogues

T2 - novel 5-HT(2A)/5-HT(2C) receptor agonists with pro-cognitive properties

AU - Jensen, Anders A

AU - Plath, Niels

AU - Pedersen, Martin H. F.

AU - Isberg, Vignir

AU - Krall, Jacob

AU - Wellendorph, Petrine

AU - Stensbøl, Tine B.

AU - Gloriam, David E.

AU - Krogsgaard-Larsen, Povl

AU - Frølund, Bente

PY - 2013/2/14

Y1 - 2013/2/14

N2 - 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.

AB - 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.

KW - Azepines

KW - Biological Availability

KW - Cognition

KW - Drug Design

KW - HEK293 Cells

KW - Humans

KW - Receptor, Serotonin, 5-HT2A

KW - Receptor, Serotonin, 5-HT2C

KW - Serotonin Receptor Agonists

U2 - 10.1021/jm301656h

DO - 10.1021/jm301656h

M3 - Journal article

C2 - 23301527

SN - 0022-2623

VL - 56

SP - 1211

EP - 1227

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 3

ER -