ANALOGS OF THE LOW-EFFICACY PARTIAL GABA-A AGONIST 4-PIOL - SYNTHESES AND INVITRO 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 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 H-3-GABA(A) or the subunit-selective GABA(A) agonist, H-3-THIP, to GABA(A) receptor sites, and they did not significantly affect the muscimol-stimulated binding of H-3-diazepam to the benzodiazepine site of the GABA(A) receptor complex.}