組換えGABA（C）受容体におけるGABAのシクロペンタンおよびシクロペンチン類似体の効果

CIS-3-アミノサイクロペンタンカルボン酸（（+） - および（ - ） - CACP）のエナンチオマーの薬理学的効果、トランス-3-アミノサイクロペンタネカルボン酸のエナンチオマー（（+） - および（ - ） - TACP）、および4-アミノサイクロペント-1-Ene-1-カルボン酸（（+） - および（ - ） - 4-ACPCA）のエナンチオマーは、Xenopusで発現したヒト同性Rho（1）およびRho（2）GABA（C）受容体で研究されました。2電極電圧クランプ法を使用した卵母細胞。These compounds are conformationally restricted analogues of gamma-aminobutyric acid (GABA) held in a five-membered ring.(+)-TACP (EC(50) (rho(1))=2.7+/-0.2 microM; EC(50) (rho(2))=1.45+/-0.22 microM), (+)-CACP (EC(50) (rho(1))=26.1+/-1.1 microM; EC(50) (rho(2))=20.1+/-2.1 microM) and (-)-CACP (EC(50) (rho(1))=78.5+/-3.5 microM; EC(50) (rho(2))=63.8+/-23.3 microM) were moderately potent partial agonists at rho(1) and rho(2) GABA(C) receptors, while（ - ） - TACP（100ミクロムは、それぞれRho（1）およびRho（2）受容体で1ミクロムGABAによって生成される電流の56％および62％を阻害しました）は、これらの受容体での内因性活性が低い弱い部分アゴニストでした。In contrast, (+)-4-ACPCA (K(i) (rho(1))=6.0+/-0.1 microM; K(i) (rho(2))=4.7+/-0.3 microM) did not activateGABA（C）Rho（1）およびRho（2）受容体はこれらの受容体でのGABAの作用を強力に阻害しましたが、（ - ）-4-ACPCAはアゴニストまたは拮抗薬としてはほとんど効果がありませんでした。The affinity order at both GABA(C) rho(1) and rho(2) receptors was (+)-TACP>(+)-4-ACPCA >> (+)-CACP>(-)-CACP >> (-)-TACP >> (-)-4-ACPCA.この研究は、GABAのシクロペンタンとシクロペンチン類似体がGABA（C）受容体にユニークな方法で影響を及ぼし、GABA（C）受容体に結合する際にアミンおよびカルボン酸基の好ましい立体化学的配向を定義することを示しています。This is exemplified by the partial agonist, (+)-TACP, and the antagonist, (+)-4-ACPCA.

The pharmacological effects of the enantiomers of cis-3-aminocyclopentanecarboxylic acids ((+)- and (-)-CACP), the enantiomers of trans-3-aminocyclopentanecarboxylic acids ((+)- and (-)-TACP), and the enantiomers of 4-aminocyclopent-1-ene-1-carboxylic acids ((+)- and (-)-4-ACPCA) were studied on human homomeric rho(1) and rho(2) GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp methods. These compounds are conformationally restricted analogues of gamma-aminobutyric acid (GABA) held in a five-membered ring. (+)-TACP (EC(50) (rho(1))=2.7+/-0.2 microM; EC(50) (rho(2))=1.45+/-0.22 microM), (+)-CACP (EC(50) (rho(1))=26.1+/-1.1 microM; EC(50) (rho(2))=20.1+/-2.1 microM) and (-)-CACP (EC(50) (rho(1))=78.5+/-3.5 microM; EC(50) (rho(2))=63.8+/-23.3 microM) were moderately potent partial agonists at rho(1) and rho(2) GABA(C) receptors, while (-)-TACP (100 microM inhibited 56% and 62% of the current produced by 1 microM GABA at rho(1) and rho(2) receptors, respectively) was a weak partial agonist with low intrinsic activity at these receptors. In contrast, (+)-4-ACPCA (K(i) (rho(1))=6.0+/-0.1 microM; K(i) (rho(2))=4.7+/-0.3 microM) did not activate GABA(C) rho(1) and rho(2) receptors but potently inhibited the action of GABA at these receptors, while (-)-4-ACPCA had little effect as either an agonist or an antagonist. The affinity order at both GABA(C) rho(1) and rho(2) receptors was (+)-TACP>(+)-4-ACPCA >> (+)-CACP>(-)-CACP >> (-)-TACP >> (-)-4-ACPCA. This study shows that the cyclopentane and cyclopentene analogues of GABA affect GABA(C) receptors in a unique manner, defining a preferred stereochemical orientation of the amine and carboxylic acid groups when binding to GABA(C) receptors. This is exemplified by the partial agonist, (+)-TACP, and the antagonist, (+)-4-ACPCA.