Duke R K, Chebib M, Balcar V J, Allan R D, Mewett K N, Johnston G A
Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, University of Sydney, New South Wales, Australia.
J Neurochem. 2000 Dec;75(6):2602-10. doi: 10.1046/j.1471-4159.2000.0752602.x.
The effects of the enantiomers of (+/-)-CAMP and (+/-)-TAMP [(+/-)-cis- and (+/-)-trans-2-aminomethylcyclopropanecarboxylic acids, respectively], which are cyclopropane analogues of GABA, were tested on GABA(A) and GABA(C) receptors expressed in Xenopus laevis oocytes using two-electrode voltage clamp methods. (+)-CAMP was found to be a potent and full agonist at homooligomeric GABA(C) receptors (K:(D) approximately 40 microM: and I:(max) approximately 100% at rho(1); K:(D) approximately 17 microM: and I:(max) approximately 100% at rho(2)) but a very weak antagonist at alpha(1)beta(2)gamma(2L) GABA(A) receptors. In contrast, (-)-CAMP was a very weak antagonist at both alpha(1)beta(2)gamma(2L) GABA(A) receptors and homooligomeric GABA(C) receptors (IC(50) approximately 900 microM: at rho(1) and approximately 400 microM: at rho(2)). Furthermore, (+)-CAMP appears to be a superior agonist to the widely used GABA(C) receptor partial agonist cis-4-aminocrotonic acid (K:(D) approximately 74 microM: and I:(max) approximately 78% at rho(1); K:(D) approximately 70 microM: and I:(max) approximately 82% at rho(2)). (-)-TAMP was the most potent of the cyclopropane analogues on GABA(C) receptors (K:(D) approximately 9 microM: and I:(max) approximately 40% at rho(1); K:(D) approximately 3 microM: and I:(max) approximately 50-60% at rho(2)), but it was also a moderately potent GABA(A) receptor partial agonist (K:(D) approximately 50-60 microM: and I:(max) approximately 50% at alpha(1)beta(2)gamma(2L) GABA(A) receptors). (+)-TAMP was a less potent partial agonist at GABA(C) receptors (K:(D) approximately 60 microM: and I:(max) approximately 40% at rho(1); K:(D) approximately 30 microM: and I:(max) approximately 60% at rho(2)) and a weak partial agonist at alpha(1)beta(2)gamma(2L) GABA(A) receptors (K:(D) approximately 500 micro: and I:(max) approximately 50%). None of the isomers of (+/-)-CAMP and (+/-)-TAMP displayed any interaction with GABA transport at the concentrations tested. Molecular modeling based on the present results provided new insights into the chiral preferences for either agonism or antagonism at GABA(C) receptors.
（±）-CAMP和（±）-TAMP的对映体（分别为（±）-顺式和（±）-反式-2-氨基甲基环丙烷羧酸）是GABA的环丙烷类似物，使用双电极电压钳方法在非洲爪蟾卵母细胞中表达的GABA(A)和GABA(C)受体上测试了它们的作用。发现（+）-CAMP是同源寡聚GABA(C)受体的强效完全激动剂（在rho(1)处，K:(D)约为40 microM，I:(max)约为100%；在rho(2)处，K:(D)约为17 microM，I:(max)约为100%），但在α(1)β(2)γ(2L) GABA(A)受体上是非常弱的拮抗剂。相反，（-）-CAMP在α(1)β(2)γ(2L) GABA(A)受体和同源寡聚GABA(C)受体上都是非常弱的拮抗剂（在rho(1)处IC(50)约为900 microM，在rho(2)处约为400 microM）。此外，（+）-CAMP似乎是比广泛使用的GABA(C)受体部分激动剂顺式-4-氨基巴豆酸更好的激动剂（在rho(1)处，K:(D)约为74 microM，I:(max)约为78%；在rho(2)处，K:(D)约为70 microM，I:(max)约为82%）。（-）-TAMP是环丙烷类似物中对GABA(C)受体最有效的（在rho(1)处，K:(D)约为9 microM，I:(max)约为40%；在rho(2)处，K:(D)约为3 microM，I:(max)约为50 - 60%），但它也是一种中等效力的GABA(A)受体部分激动剂（在α(1)β(2)γ(2L) GABA(A)受体处，K:(D)约为50 - 60 microM，I:(max)约为50%）。（+）-TAMP是GABA(C)受体上效力较低的部分激动剂（在rho(1)处，K:(D)约为60 microM，I:(max)约为40%；在rho(2)处，K:(D)约为30 microM，I:(max)约为60%），在α(1)β(2)γ(2L) GABA(A)受体上是弱部分激动剂（K:(D)约为500 microM，I:(max)约为50%）。在测试浓度下，（±）-CAMP和（±）-TAMP的任何异构体均未显示与GABA转运有任何相互作用。基于目前结果的分子建模为GABA(C)受体激动或拮抗的手性偏好提供了新的见解。
