Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory.
Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory.
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DOI：
10.1124/jpet.108.146464
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发表时间：
2009-02
影响因子：
3.5
通讯作者：
Hanrahan, Jane R.
中科院分区：
文献类型：
--
作者：
Chebib, Mary;Hinton, Tina;Schmid, Katrina L.;Brinkworth, Darren;Qian, Haohua;Matos, Susana;Kim, Hye-Lim;Abdel-Halim, Heba;Kumar, Rohan J.;Johnston, Graham A. R.;Hanrahan, Jane R.
本研究报道顺式和反式-（3-氨基环戊基）丁基膦酸（顺式和反式-3- acpbpa）的药理和生理作用。这些化合物是口服活性GABAB/C受体拮抗剂（3-氨基丙基）-正丁基膦酸（CGP36742或SGS742）构象受限的类似物。Cis- (IC50(ρ1)=5.06μM, IC50(ρ2)=11.08μM；n=4), trans-3-ACPMPA (IC50(ρ1)=72.58μM, IC50(ρ2)=189.7 μM；n=4)对爪蟾卵母细胞中表达的GABAC受体具有竞争性，作为激动剂（1 mM）没有作用，但对人GABAA和GABAB受体具有弱拮抗剂（1 mM）作用。顺式-3- acpbpa比反式化合物更有效和选择性，对GABAC的效力是GABAA或GABAB受体的100倍以上。顺式-3- ACPBPA对游离大鼠视网膜双极细胞的抑制作用呈剂量依赖性（IC50=47±4.5μM; n=6）。在鸡模型中，顺式和反式3- acpbpa以剂量依赖的方式应用于眼玻璃体内注射，可防止实验性近视的发展，并抑制相关的玻璃体腔伸长。仅比抑制重组GABAC受体所需的剂量大10倍就能产生抗近视效果。通过腹腔注射，顺式- (30 mg/kg)和反式-3- acpbpa （100 mg/kg）增强雄性Wistar大鼠的学习和记忆能力；Morris水迷宫任务中，大鼠找到平台的时间显著缩短（n=10; p<0.05）。由于顺式和反式3-ACPBPA的生理作用与CGP36742相似，CGP36742的记忆和折射效应可能部分归因于其GABAC活性。
This study reports pharmacological and physiological effects of cis- and trans-(3-aminocyclopentanyl)butylphosphinic acid (cis- and trans-3-ACPBPA). These compounds are conformationally restricted analogs of the orally active GABAB/C receptor antagonist, (3- aminopropyl)-n-butylphosphinic acid (CGP36742 or SGS742). Cis- (IC50(ρ1)=5.06μM and IC50(ρ2)=11.08μM; n=4) and trans-3-ACPMPA (IC50(ρ1)=72.58μM and IC50(ρ2)=189.7 μM; n=4) appear competitive at GABAC receptors expressed in Xenopus oocytes, having no effect as agonists (1 mM) but exerting weak antagonist (1 mM) effects on human GABAA and GABAB receptors. Cis-3-ACPBPA was more potent and selective than the trans compound being over 100-times more potent at GABAC than GABAA or GABAB receptors. Cis-3- ACPBPA was further evaluated on dissociated rat retinal bipolar cells and dose dependently inhibited the native GABAC receptor (IC50=47±4.5μM; n=6). When applied to the eye as intravitreal injections, cis- and trans-3-ACPBPA prevented experimental myopia development, and inhibited the associated vitreous chamber elongation, in a dose dependent manner in the chick model. Doses only 10-times greater than required to inhibit recombinant GABAC receptors caused the anti-myopia effects. Using intraperitoneal administration, cis- (30 mg/kg) and trans-3-ACPBPA (100 mg/kg) enhanced learning and memory in male Wistar rats; compared to vehicle there was a significant reduction in time for rats to find the platform in the Morris Water Maze task (n=10; p<0.05). As the physiological effects of cis- and trans- 3-ACPBPA are similar to those reported for CGP36742, the memory and refractive effects of CGP36742 may be due in part to its GABAC activity.
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影响因子：
3.3
作者：
Gibbs, ME;Johnston, GAR
通讯作者：
Johnston, GAR
影响因子：
3.2
作者：
Hanrahan, Jane R.;Mewett, Kenneth N.;Johnston, Graham A. R.
通讯作者：
Johnston, Graham A. R.
影响因子：
4.7
作者：
Duke, RK;Chebib, M;Johnston, GAR
通讯作者：
Johnston, GAR
影响因子：
--
作者：
Lummis, SCR;Beene, DL;Dougherty, DA
通讯作者：
Dougherty, DA
影响因子：
4.4
作者：
Ramsey, David J.;Ripps, Harris;Qian, Haohua
通讯作者：
Qian, Haohua