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

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.