Phosphinic, phosphonic and seleninic acid bioisosteres of isonipecotic acid as novel and selective GABAC receptor antagonists

被引：18
作者：
Krehan, D
Frolund, B
Krogsgaard-Larsen, P
Kehler, J
Johnston, GAR
Chebib, M
机构：
[1] Royal Danish Sch Pharm, Dept Med Chem, Ctr Drug Design & Transport, DK-2100 Copenhagen, Denmark
[2] H Lundbeck & Co AS, Dept Med Chem, DK-2500 Valby, Denmark
[3] Univ Sydney, Dept Pharmacol, Adrien Albert Lab Med Chem, Sydney, NSW 2006, Australia
[4] Univ Sydney, Fac Pharm, Sydney, NSW 2006, Australia
来源：
NEUROCHEMISTRY INTERNATIONAL | 2003年 / 42卷 / 07期
关键词：
GABA(C) receptors; homomeric receptors; GABA(C) antagonists; bioisosteres; isonipecotic acid isosteres; electrophysiology; Xenopus oocytes;
D O I：
10.1016/S0197-0186(02)00162-6
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
A number of amino acids bioisosterically derived from the specific GABA(A) agonist, isonipecotic acid, were electrophysiologically characterized as antagonists at GABA(C) rho(1) receptors expressed in Xenopus oocytes. The phosphinic acid analogue of isonipecotic acid, piperidin-4-ylphosphinic acid (2), was comparable with the standard GABA(C) antagonist, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), in terms of potency and GABAC versus GABAA receptor selectivity. Whereas the phosphonic acid analogue, piperidin-4-ylphosphonic acid (4), was at least an order of magnitude weaker than piperidin-4-ylphosphinic acid as a GABAC antagonist, the seleninic acid analogue, piperidin-4-ylseleninic acid (SEPI, 6), was the most potent and selective GABAC antagonist within the group of isonipecotic acid derived amino acids studied. (C) 2003 Elsevier Science Ltd. All rights reserved.
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收藏
页码：561 / 565
页数：5
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