富马酸戊乙奎醚消旋体(R,R')-光学异构体及其溴化季铵盐对M1和M3受体亚型亲和力的比较

摘要

目的 比较富马酸戊乙奎醚消旋体、(R,R’)-光学异构体及其溴化季铵盐对M1和M3受体亚型的亲和力.方法 应用放射性配体受体饱和实验测定[氚]N-甲基东莨菪碱([3H]-NMS)对M1和M3受体亚型的最大结合力及平衡解离常数,竞争性抑制试验比较富马酸戊乙奎醚消旋体、(R,R’)-光学异构体及其溴化季铵盐对M1和M3受体亚型的亲和力.结果 [3H] -NMS对M1和M3的最大结合力(Bmax)值分别为(2.8±0.22)、(3.6±0.14) pmol/mg,平衡解离常数(Kd)值分别为(0.29±0.04)×10-9、(0.53±0.09)×10-9 moL/L.富马酸戊乙奎醚消旋体、(R,R’)-光学异构体及其溴化季铵盐对M1受体的竞争抑制平衡解离常数(Ki)依次为(2.54±0.71) ×10-11、(3.86±0.94)×10-12、(6.73±1.71)×10-11mol/L,对M3受体的Ki依次为(1.06±0.57) ×10-11、(1.97±0.85) ×10-12、(2.94±0.53)×10-11mol/L.结论 环丙甲基戊乙奎醚溴化季铵盐对M1和M3受体亚型的亲和力低于富马酸戊乙奎醚消旋体及其(R,R’)-光学异构体,但对M3受体亚型仍具有高选择性.%Objective To investigate the affinity to Ml and M3 receptor subtypes of penehydidine fumarate racemate, ( R,R')-optical isomer and its bromination quaternary ammonium salt. Methods The affinity and satura-bility of [3H] N-methylscopolamine( [3H]-NMS) to Ml and M3 receptor subtypes were obtained by radioligand saturation binding assay. Competitive inhibition experiments analyzed the affinities to Ml and M3 receptor subtypes of penehydidine fumarate racemate, ( R,R')-optical isomer and its bromination quaternary ammonium salt. Results The maximum binding capacity(Bmax) of [3H]-NMS to Ml and M3 receptor subtypes was (2.8 ±0.22) ,(3.6 ± 0.14) pmol/mg,and the dissociation equilibrium constant (Kd) value was (0.29 ±0.04) × 10-9,(0.53 ±0.09) ×10-9 mol/L, respectively. The competitive inhibition equilibrium dissociation constant (Ki) to Ml receptor subtypes of penehydidine fumarate racemate, ( R, R')-optical isomer and its bromination quaternary ammonium salt was (2.54 ±0.71) ×10-11 , (3. 86 ±0.94) × 10-12, (6.73 ± 1.71) × 10 -11 mol/L. The Ki to M3 receptor subtypes was (1.06±0.57) × 10-11 ,(1.97 ±0. 85) × 10-12,(2.94 ±0.53) × 10-11 mol/L, respectively. Conclusion The affinities to Ml and M3 receptor subtypes of penehydidine fumarate racemate bromination quaternary ammonium salt were lower than those of penehydidine fumarate racemate and its ( R,R')-optical isomer, but its selectivity to M3 remained high.