3-hydroxyisoxazole bioiosteres of gaba - synthesis of a series of 4-substituted muscimol analogs and identification of a bicyclic 2-isoxazoline rearrangement product

Research output: Contribution to journalJournal articlepeer-review

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3-hydroxyisoxazole bioiosteres of gaba - synthesis of a series of 4-substituted muscimol analogs and identification of a bicyclic 2-isoxazoline rearrangement product. / Hjeds, H.; Christensen, I. T.; Cornett, Claus; Frolund, B.; Falch, E.; Pedersen, J. B.; Krogsgaardlarsen, P.

In: Acta Chemica Scandinavica. Supplementum, Vol. 46, No. 8, 1992, p. 772-777.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Hjeds, H, Christensen, IT, Cornett, C, Frolund, B, Falch, E, Pedersen, JB & Krogsgaardlarsen, P 1992, '3-hydroxyisoxazole bioiosteres of gaba - synthesis of a series of 4-substituted muscimol analogs and identification of a bicyclic 2-isoxazoline rearrangement product', Acta Chemica Scandinavica. Supplementum, vol. 46, no. 8, pp. 772-777.

APA

Hjeds, H., Christensen, I. T., Cornett, C., Frolund, B., Falch, E., Pedersen, J. B., & Krogsgaardlarsen, P. (1992). 3-hydroxyisoxazole bioiosteres of gaba - synthesis of a series of 4-substituted muscimol analogs and identification of a bicyclic 2-isoxazoline rearrangement product. Acta Chemica Scandinavica. Supplementum, 46(8), 772-777.

Vancouver

Hjeds H, Christensen IT, Cornett C, Frolund B, Falch E, Pedersen JB et al. 3-hydroxyisoxazole bioiosteres of gaba - synthesis of a series of 4-substituted muscimol analogs and identification of a bicyclic 2-isoxazoline rearrangement product. Acta Chemica Scandinavica. Supplementum. 1992;46(8):772-777.

Author

Hjeds, H. ; Christensen, I. T. ; Cornett, Claus ; Frolund, B. ; Falch, E. ; Pedersen, J. B. ; Krogsgaardlarsen, P. / 3-hydroxyisoxazole bioiosteres of gaba - synthesis of a series of 4-substituted muscimol analogs and identification of a bicyclic 2-isoxazoline rearrangement product. In: Acta Chemica Scandinavica. Supplementum. 1992 ; Vol. 46, No. 8. pp. 772-777.

Bibtex

@article{32f502c97a36469284993430c5aad76c,
title = "3-hydroxyisoxazole bioiosteres of gaba - synthesis of a series of 4-substituted muscimol analogs and identification of a bicyclic 2-isoxazoline rearrangement product",
abstract = "3-Hydroxy-4-(2-hydroxyethyl)-5-methylisoxazole (1) was used as the starting material for the syntheses of the muscimol (5-aminomethyl-3-hydroxyisoxazole) analogues 9, 10 and 14, containing 2-acetoxyethyl, 2-hydroxyethyl, and 2-chloroethyl substituents, respectively, in the 4-position of the ring. These analogues were synthesized via bromination of the 5-methyl groups of the di-O-protected derivative of 1 (5) followed by a Gabriel phthalimide reaction. N-Deprotection of 4-(2-chloroethyl)-3-methoxy-5-phthalimidomethylisoxazole (12), an intermediate for the preparation of 14, followed by cyclization and O-deprotection form the last steps of a new synthesis of the clinically active bicyclic muscimol analogue, (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol) (THIP) (16). Whereas treatment of 4-(2-hydroxyethyl)-3-methoxy-5-methylisoxazole (3a) with bromine or with NBS gave the bicyclic 2-isoxazoline 17a. A similar treatment of the 4-(3-hydroxypropyl) homologue (3b) of 3a did not provide the 6-membered ring analogue of 17a (17b). Whilst muscimol and THIP are very potent agonists at GABA(A) receptors, none of the muscimol analogues 9, 10 or 14 showed significant affinity for GABA(A) receptor sites in vitro.",
keywords = "tardive-dyskinesia huntingtons-disease thip agonists modulation membranes neurons binding acid",
author = "H. Hjeds and Christensen, {I. T.} and Claus Cornett and B. Frolund and E. Falch and Pedersen, {J. B.} and P. Krogsgaardlarsen",
year = "1992",
language = "Udefineret/Ukendt",
volume = "46",
pages = "772--777",
journal = "Acta Chemica Scandinavica. Supplementum",
issn = "0065-1133",
publisher = "Acta Chemica Scandinavica. Supplementum",
number = "8",

}

RIS

TY - JOUR

T1 - 3-hydroxyisoxazole bioiosteres of gaba - synthesis of a series of 4-substituted muscimol analogs and identification of a bicyclic 2-isoxazoline rearrangement product

AU - Hjeds, H.

AU - Christensen, I. T.

AU - Cornett, Claus

AU - Frolund, B.

AU - Falch, E.

AU - Pedersen, J. B.

AU - Krogsgaardlarsen, P.

PY - 1992

Y1 - 1992

N2 - 3-Hydroxy-4-(2-hydroxyethyl)-5-methylisoxazole (1) was used as the starting material for the syntheses of the muscimol (5-aminomethyl-3-hydroxyisoxazole) analogues 9, 10 and 14, containing 2-acetoxyethyl, 2-hydroxyethyl, and 2-chloroethyl substituents, respectively, in the 4-position of the ring. These analogues were synthesized via bromination of the 5-methyl groups of the di-O-protected derivative of 1 (5) followed by a Gabriel phthalimide reaction. N-Deprotection of 4-(2-chloroethyl)-3-methoxy-5-phthalimidomethylisoxazole (12), an intermediate for the preparation of 14, followed by cyclization and O-deprotection form the last steps of a new synthesis of the clinically active bicyclic muscimol analogue, (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol) (THIP) (16). Whereas treatment of 4-(2-hydroxyethyl)-3-methoxy-5-methylisoxazole (3a) with bromine or with NBS gave the bicyclic 2-isoxazoline 17a. A similar treatment of the 4-(3-hydroxypropyl) homologue (3b) of 3a did not provide the 6-membered ring analogue of 17a (17b). Whilst muscimol and THIP are very potent agonists at GABA(A) receptors, none of the muscimol analogues 9, 10 or 14 showed significant affinity for GABA(A) receptor sites in vitro.

AB - 3-Hydroxy-4-(2-hydroxyethyl)-5-methylisoxazole (1) was used as the starting material for the syntheses of the muscimol (5-aminomethyl-3-hydroxyisoxazole) analogues 9, 10 and 14, containing 2-acetoxyethyl, 2-hydroxyethyl, and 2-chloroethyl substituents, respectively, in the 4-position of the ring. These analogues were synthesized via bromination of the 5-methyl groups of the di-O-protected derivative of 1 (5) followed by a Gabriel phthalimide reaction. N-Deprotection of 4-(2-chloroethyl)-3-methoxy-5-phthalimidomethylisoxazole (12), an intermediate for the preparation of 14, followed by cyclization and O-deprotection form the last steps of a new synthesis of the clinically active bicyclic muscimol analogue, (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol) (THIP) (16). Whereas treatment of 4-(2-hydroxyethyl)-3-methoxy-5-methylisoxazole (3a) with bromine or with NBS gave the bicyclic 2-isoxazoline 17a. A similar treatment of the 4-(3-hydroxypropyl) homologue (3b) of 3a did not provide the 6-membered ring analogue of 17a (17b). Whilst muscimol and THIP are very potent agonists at GABA(A) receptors, none of the muscimol analogues 9, 10 or 14 showed significant affinity for GABA(A) receptor sites in vitro.

KW - tardive-dyskinesia huntingtons-disease thip agonists modulation membranes neurons binding acid

M3 - Tidsskriftartikel

VL - 46

SP - 772

EP - 777

JO - Acta Chemica Scandinavica. Supplementum

JF - Acta Chemica Scandinavica. Supplementum

SN - 0065-1133

IS - 8

ER -

ID: 38061437