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

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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.
Original languageUndefined/Unknown
JournalActa Chemica Scandinavica. Supplementum
Issue number8
Pages (from-to)772-777
Number of pages6
Publication statusPublished - 1992

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