Analogues of the low-efficacy partial GABAA agonist 4-PIOL. Syntheses and in vitro pharmacological studies
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Analogues of the low-efficacy partial GABAA agonist 4-PIOL. Syntheses and in vitro pharmacological studies. / De Amici, M.; Frølund, B.; Hjeds, H.; Krogsgaard-Larsen, P.
In: European Journal of Medicinal Chemistry, Vol. 26, No. 6, 09.1991, p. 625-631.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Analogues of the low-efficacy partial GABAA agonist 4-PIOL. Syntheses and in vitro pharmacological studies
AU - De Amici, M.
AU - Frølund, B.
AU - Hjeds, H.
AU - Krogsgaard-Larsen, P.
PY - 1991/9
Y1 - 1991/9
N2 - 4-PIOL (3-hydroxy-5-(4-piperidyl)isoxazole) is a low-efficacy GABAA agonist showing a dominating GABAA 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-GABAA or the subunit-selective GABAA agonist, 3H-THIP, to GABAA receptor sites, and they did not significantly affect the muscimol-stimulated binding of 3H-diazepam to the benzodiazepine site of the GABAA receptor complex.
AB - 4-PIOL (3-hydroxy-5-(4-piperidyl)isoxazole) is a low-efficacy GABAA agonist showing a dominating GABAA 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-GABAA or the subunit-selective GABAA agonist, 3H-THIP, to GABAA receptor sites, and they did not significantly affect the muscimol-stimulated binding of 3H-diazepam to the benzodiazepine site of the GABAA receptor complex.
KW - 3-hydroxy-2-isoxazoline spiro compounds
KW - 3-hydroxy-2-isoxazolines
KW - 4-PIOL analogues
KW - bromonitrile oxide
KW - cycloaddition reactions
KW - dibromoformoxime
KW - GABA receptors
KW - partial GABA agonists
KW - THIP analogues
UR - http://www.scopus.com/inward/record.url?scp=0025942730&partnerID=8YFLogxK
U2 - 10.1016/0223-5234(91)90198-V
DO - 10.1016/0223-5234(91)90198-V
M3 - Journal article
AN - SCOPUS:0025942730
VL - 26
SP - 625
EP - 631
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
IS - 6
ER -
ID: 312699514