Lysíková M, Fuksová K, Elbert T, Jakubík J, Tucek S
Institute of Physiology, Academy of Sciences of the Czech Republic, Prague.
Br J Pharmacol. 1999 Jul;127(5):1240-6. doi: 10.1038/sj.bjp.0702646.
Seven esters of alpha-truxillic acid have been synthesized: bis-3-piperidylpropyl ester and its quaternary bis-N-ethyl derivative, bis-N-diethylaminopropyl ester and its quaternary bis-N-methyl derivative, and bis-4-piperidylbutyl ester and its quaternary bis-N-methyl and bis-N-ethyl derivatives. All esters inhibited the specific binding of muscarinic receptor antagonist [methyl-3H]-N-methylscopolamine ([3H]-NMS) to muscarinic receptors in membranes of CHO cell lines stably expressing the human gene for the M1, M2, M3 or M4 subtype of muscarinic receptors. All esters displayed the highest potency at the M2 and the lowest potency at the M3 receptor subtype. In experiments performed on the M2 muscarinic receptor subtype, the affinity between the receptors and the esters was greatly increased when the concentration of ions was diminished. The highest affinities were found for the tertiary bis-3-piperidylpropyl and bis-4-piperidylbutyl aminoesters (equilibrium dissociation constants of 52 and 179 pM, respectively, in the low ionic strength medium). All investigated esters slowed down the dissociation of [3H]-NMS from the M2 muscarinic receptor subtype. [3H]-NMS dissociation from the M1, M3 and M4 muscarinic receptor subtypes was investigated in experiments with the bis-4-piperidylbutyl aminoester and also found to be decelerated. It is concluded that the esters of alpha-truxillic acid act as M2-selective allosteric modulators of muscarinic receptors and that, by their potency, the tertiary bis-3-piperidylpropyl and bis-4-piperidylbutyl aminoesters surpass the other known allosteric modulators of these receptors.
已合成了七种α-曲辛二酸酯：双-3-哌啶基丙酯及其季铵双-N-乙基衍生物、双-N-二乙氨基丙酯及其季铵双-N-甲基衍生物、双-4-哌啶基丁酯及其季铵双-N-甲基和双-N-乙基衍生物。所有酯均抑制毒蕈碱受体拮抗剂[甲基-³H]-N-甲基东莨菪碱（[³H]-NMS）与稳定表达毒蕈碱受体M1、M2、M3或M4亚型人类基因的CHO细胞系膜中毒蕈碱受体的特异性结合。所有酯在M2受体亚型上显示出最高效力，在M3受体亚型上效力最低。在对M2毒蕈碱受体亚型进行的实验中，当离子浓度降低时，受体与酯之间的亲和力大大增加。叔双-3-哌啶基丙酯和双-4-哌啶基丁酯氨基酯具有最高亲和力（在低离子强度介质中，平衡解离常数分别为52和179 pM）。所有研究的酯均减缓了[³H]-NMS从M2毒蕈碱受体亚型上的解离。在用双-4-哌啶基丁酯氨基酯进行的实验中，还研究了[³H]-NMS从M1、M3和M4毒蕈碱受体亚型上的解离，结果发现其也被减缓。得出的结论是，α-曲辛二酸酯作为毒蕈碱受体的M2选择性变构调节剂，并且就其效力而言，叔双-3-哌啶基丙酯和双-4-哌啶基丁酯氨基酯超过了这些受体的其他已知变构调节剂。
