Synthesis and pharmacological evaluation of cis-2,3,3a,4,5,6,7,7a-octahydro-3-oxoisoxazolo[5,4-c]pyridine: a structural analogue of the GABA agonist THIP.

The pharmacological activities of the GABA agonist muscimol (1) and its dihydro analogue (2) have been shown to be almost identical. The closely related 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 3), although biologically less active than muscimol, was selected for clinical trials. We report the synthesis of the so far elusive cis-2,3,3a,4,5,6,7,7a-octahydro-3-oxoisoxazolo[5,4-c]pyridine (cis-DH-THIP, cis-4), which--surprisingly--is devoid of any GABAergic activity.