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.}

ANALOGS OF THE LOW-EFFICACY PARTIAL GABA-A AGONIST 4-PIOL - SYNTHESES AND INVITRO PHARMACOLOGICAL STUDIES / M. De Amici, B. Frolund, H. Hjeds, P. Krogsgaard-Larsen. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 26:6(1991), pp. 625-631.

ANALOGS OF THE LOW-EFFICACY PARTIAL GABA-A AGONIST 4-PIOL - SYNTHESES AND INVITRO PHARMACOLOGICAL STUDIES

M. De Amici;
1991

Abstract

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.}
GABA-A RECEPTORS; PARTIAL GABA-A AGONISTS; THIP ANALOGS; 4-PIOL ANALOGS; 3-HYDROXY-2-ISOXAZOLINES; 3-HYDROXY-2-ISOXAZOLINE SPIRO COMPOUNDS; CYCLOADDITION REACTIONS; DIBROMOFORMOXIME; BROMONITRILE OXIDE
Settore CHIM/08 - Chimica Farmaceutica
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/184399
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