Crittenden Deborah L, Park Anna, Qiu Jian, Silverman Richard B, Duke Rujee K, Johnston Graham A R, Jordan Meredith J T, Chebib Mary
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Bioorg Med Chem. 2006 Jan 15;14(2):447-55. doi: 10.1016/j.bmc.2005.08.037. Epub 2005 Sep 23.
The effects of the enantiomers of a number of flexible and cis-constrained GABA analogues were tested on GABA(C) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (1S,2R)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((+)-CAMP), a potent and full agonist at the rho1 (EC(50) approximately 40 microM, I(max) approximately 100%) and rho 2 (EC(50) approximately 17 microM, I(max) approximately 100%) receptor subtypes, was found to be a potent partial agonist at rho3 (EC(50) approximately 28 microM, I(max) approximately 70%). (1R,2S)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((-)-CAMP), a weak antagonist at human rho1 (IC(50) approximately 890 microM) and rho2 (IC(50) approximately 400 microM) receptor subtypes, was also found to be a moderately potent antagonist at rat rho3 (IC(50) approximately 180 microM). Similarly, (1R,4S)-4-aminocyclopent-2-ene-1-carboxylic acid ((+)-ACPECA) was a full agonist at rho1 (EC(50) approximately 135 microM, I(max) approximately 100%) and rho2 (EC(50) approximately 60 microM, I(max) approximately 100%), but only a partial agonist at rho3 (EC(50) approximately 112 microM, I(max) approximately 37%), while (1S,4R)-4-aminocyclopent-2-ene-1-carboxylic acid ((-)-ACPECA) was a weak antagonist at all three receptor subtypes (IC(50)>>300 microM). 4-Amino-(S)-2-methylbutanoic acid ((S)-2MeGABA) and 4-amino-(R)-2-methylbutanoic acid ((R)-2MeGABA) followed the same trend, with (S)-2MeGABA acting as a full agonist at the rho1 (EC(50) approximately 65 microM, I(max) approximately 100%), and rho2 (EC(50) approximately 20 microM, I(max) approximately 100%) receptor subtypes, and a partial agonist at rho3 (EC(50) approximately 25 microM, I(max) approximately 90%). (R)-2MeGABA, however, was a moderately potent antagonist at all three receptor subtypes (IC(50) approximately 16 microM at rho1, 125 microM at rho2 and 35 microM at rho3). On the basis of these expanded biological activity data and the solution-phase molecular structures obtained at the MP2/6-31+G* level of ab initio theory, a rationale is proposed for the genesis of this stereoselectivity effect.
利用双电极电压钳电生理学方法，在非洲爪蟾卵母细胞中表达的γ-氨基丁酸C型（GABA(C)）受体上测试了多种柔性和顺式构象受限的GABA类似物对映体的作用。（1S,2R）-顺式-2-氨甲基环丙烷-1-羧酸（（+）-CAMP）是rho1（半数有效浓度（EC(50)）约为40微摩尔，最大效应（I(max)）约为100%）和rho2（EC(50)约为17微摩尔，I(max)约为100%）受体亚型的强效完全激动剂，结果发现它是rho3（EC(50)约为28微摩尔，I(max)约为70%）的强效部分激动剂。（1R,2S）-顺式-2-氨甲基环丙烷-1-羧酸（（-）-CAMP）是人类rho1（半数抑制浓度（IC(50)）约为890微摩尔）和rho2（IC(50)约为400微摩尔）受体亚型的弱拮抗剂，还发现它是大鼠rho3（IC(50)约为180微摩尔）的中度强效拮抗剂。同样，（1R,4S）-4-氨基环戊-2-烯-1-羧酸（（+）-ACPECA）是rho1（EC(50)约为135微摩尔，I(max)约为100%）和rho2（EC(50)约为60微摩尔，I(max)约为100%）的完全激动剂，但只是rho3（EC(50)约为112微摩尔，I(max)约为37%）的部分激动剂，而（1S,4R）-4-氨基环戊-2-烯-1-羧酸（（-）-ACPECA）在所有三种受体亚型中都是弱拮抗剂（IC(50)>>300微摩尔）。4-氨基-（S）-2-甲基丁酸（（S）-2MeGABA）和4-氨基-（R）-2-甲基丁酸（（R）-2MeGABA）呈现相同趋势，（S）-2MeGABA是rho1（EC(50)约为65微摩尔，I(max)约为100%）和rho2（EC(50)约为20微摩尔，I(max)约为100%）受体亚型的完全激动剂，是rho3（EC(50)约为25微摩尔，I(max)约为90%）的部分激动剂。然而，（R）-2MeGABA在所有三种受体亚型中都是中度强效拮抗剂（rho1的IC(50)约为16微摩尔，rho2的IC(50)约为125微摩尔，rho3的IC(50)约为35微摩尔）。基于这些扩展的生物活性数据以及在MP2/6 - 31 + G*从头算理论水平获得的溶液相分子结构，提出了这种立体选择性效应产生的原理。
