(+)- and (-)-cis-2-Aminomethylcyclopropanecarboxy acids show opposite pharmacology at recombinant ρ1 and ρ2 GABAC receptors
(+)- and (-)-cis-2-Aminomethylcyclopropanecarboxy acids show opposite pharmacology at recombinant ρ1 and ρ2 GABAC receptors
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DOI：
10.1046/j.1471-4159.2000.0752602.x
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发表时间：
2000-12-01
影响因子：
4.7
通讯作者：
Johnston, GAR
中科院分区：
文献类型：
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作者：
Duke, RK;Chebib, M;Johnston, GAR
(+/-)-CAMP 和 (+/-)-TAMP [分别是 (+/-)-顺式- 和 (+/-)-反式-2-氨基甲基环丙烷羧酸]（分别是 GABA 的环丙烷类似物）对映体的影响，使用 Xenopus laevis 卵母细胞中表达的 GABA(A) 和 GABA(C) 受体进行测试。 二电极电压钳法。 (+)CAMP 被发现是同寡聚 GABA(C) 受体的有效且完全激动剂（在 rho (1) 处，K-D 类似于 40 muM，I-max 类似于 100%；在 rho2 处，K-D 类似于 17 muM，I-max 类似于 100%），但对 α (1)beta (2)gamma (2L) GABA(A) 受体是非常弱的拮抗剂。相比之下，(-)-CAMP 是 α (1)β (2)gamma (2L) GABA(A) 受体和同源寡聚 GABA(C) 受体的非常弱的拮抗剂（IC50 在 rho (1) 上类似于 900 muM，在 rho (2) 上类似于 400 muM）。此外，(+)-CAMP 似乎是一种优于广泛使用的 GABA(C) 受体部分激动剂 cis-4-氨基巴豆酸的激动剂（在 rho (1) 条件下，K-D 与 74 muM 相似，I-max 与 78% 相似；在 rho (2) 条件下，K-D 与 70 muM 相似，I-max 与 82% 相似）。 (-)-TAMP 是对 GABA 受体最有效的环丙烷类似物（在 rho (1) 处，K-D 类似于 9 muM，I-max 类似于 40%；在 rho (2) 处，K-D 类似于 3 muM，I-max 类似于 50-60%），但它也是一种中等效力的 GABA(A) 受体部分激动剂（K-D 类似于 50-60 muM， I-max 类似于 50% 位于 α (1)β (2)gamma (2L) GABA(A) 受体）。 (+)-TAMP 是 GABA(C) 受体的较弱部分激动剂（在 rho (1) 处，K-D 类似于 60 muM，I-max 类似于 40%；在 rho (2) 处，K-D 类似于 30 muM，I-max 类似于 60%），并且是 α (1)beta (2)gamma (2L) GABA(A) 受体的弱部分激动剂（K-D 类似于500 μM 和 I-max 类似于 50%）。 (+/-)-CAMP 和 (+/-)-TAMP 的异构体在测试浓度下均未表现出与 GABA 转运的任何相互作用。基于目前结果的分子建模为 GABA(C) 受体的激动或拮抗手性偏好提供了新的见解。
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 similar to 40 muM and I-max similar to 100% at rho (1); K-D similar to 17 muM and I-max similar to 100% at rho2) 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 (IC50 similar to 900 muM at rho (1) and similar to 400 muM 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 similar to 74 muM and I-max similar to 78% at rho (1); K-D similar to 70 muM and I-max similar to 82% at rho (2)). (-)-TAMP was the most potent of the cyclopropane analogues on GABA, receptors (K-D similar to9 muM and I-max similar to 40% at rho (1); K-D similar to3 muM and I-max similar to 50-60% at rho (2)), but it was also a moderately potent GABA(A) receptor partial agonist (K-D similar to 50-60 muM and I-max similar to 50% at alpha (1)beta (2)gamma (2L) GABA(A) receptors). (+)-TAMP was a less potent partial agonist at GABA(C) receptors (K-D similar to 60 muM and I-max similar to 40% at rho (1); K-D similar to 30 muM and I-max similar to 60% at rho (2)) and a weak partial agonist at alpha (1)beta (2)gamma (2L) GABA(A) receptors (K-D similar to 500 muM and I-max similar to 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.