Analogues of the low-efficacy partial GABAA agonist 4-PIOL. Syntheses and in vitro pharmacological studies

Article abstract of DOI:10.1016/0223-5234(91)90198-V

4-PIOL (3-hydroxy-5-(4-piperidyl)isoxazole) is a low-efficacy GABA_A agonist showing a dominating GABA_A antagonist profile.Three dihydro analogues of 4-PIOL were synthesized, including (RS)-3-hydroxy-5-(4-piperidyl)-2-isoxazoline (1).The synthesis of 1 was based on a regioselective 1,3-dipolar cyclo-addition reaction between 1-benzyloxycarbonyl-4-vinylpiperidine (7) and bromonitrile oxide, prepared in situ from dibromoformoxime.Furthermore, the spiro analogues of 1 3-hydroxy-1-oxa-2,8-diazaspiro<4.5>dec-2-ene (2) and (RS)-3-hydroxy-1-oxa-2,7-diazaspiro<4.5>dec-2-ene (3) were synthesized regiospecifically via cycloaddition of bromonitrile oxide to the N-benzyloxycarbonyl-protected forms of 4-methylenepiperidine (11) and 3-methylenepiperidine (15) respectively.In contrast to 4-PIOL, none of the new compounds 1-3 showed detectable effects on the binding of 3H-GABA_A or the subunit-selective GABA_A agonist, 3H-THIP, to GABA_A receptor sites, and they did not significantly affect the muscimol-stimulated binding of 3H-diazepam to the benzodiazepine site of the GABA_A receptor complex.