143885-48-7Relevant academic research and scientific papers
3-Hydroxyisoxazole Bioisosteres of GABA. Synthesis of a Series of 4-Substituted Muscimol Analogues and Identification of a Bicyclic 2-Isoxazoline Rearrangement Product
Hjeds, Hans,Christensen, Inge T.,Cornett, Claus,Frolund, Bente,Falch, Erik,et al.
, p. 772 - 777 (2007/10/02)
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 of14, 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-tetrahydroisoxazolopyridin-3-ol) (THIP) (16).Whereas treatment of 4-(2-hydroxyethyl)3-methoxy-5-methylisoxazole (3a) with bromine of 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 GABAA receptors, none of the muscimol analogues 9, 10 or 14 showed significant affinity for GABAA receptor sites in vitro.
