关于两种吡咯烷衍生物的胆碱酯酶抑制特性

On the cholinesterase inhibiting properties of two pyrrolidine derivatives.

作者信息

Schuh F T

出版信息

Arzneimittelforschung. 1977;27(12):2271-3.

Abstract

The influence of cis-2-phenyl-1-pyrrolidino-cyclohexane (RX 67 668) and of cis-2-(3-hydroxyphenyl)-1-pyrrolidino-cyclohexane methobromide (RX 72 601) on acetylcholinesterase (AChE) and plasma cholinesterase (ChE) was investigated in vitro by means of a photometric assay technique with respect to their mechanism and constants of inhibition. The two compounds cause reversible inhibition of both AChE and ChE, the (I)50 and Ki for RX 67 668 being 2.5 x 10(-5) M and 4 x 10(-6) M (AChE), resp., and 2.0 x 10(-5) M and 8 x 10(-7) M (ChE), resp.; and for RX 72 601 7.9 x 10(-8) M and 3 x 10(-9) M (AChE), resp., and 3.2 x 10(-7) M and 1 x 10(-8) M (ChE), resp. The kinetic analysis of the inhibitory action disclosed a purely competitive mechanism. The inhibition of the two esterases is assumed to be induced by the formation of a readily dissociable enzyme-inhibitor complex due to the binding of the positively charged pyrrolidine moiety of the two substances to the anionic subsite of the active center, thus impairing the formation of an enzyme-substrate complex.

摘要

通过光度分析技术，在体外研究了顺式-2-苯基-1-吡咯烷基环己烷（RX 67 668）和顺式-2-（3-羟基苯基）-1-吡咯烷基环己烷甲基溴化物（RX 72 601）对乙酰胆碱酯酶（AChE）和血浆胆碱酯酶（ChE）的影响，包括其抑制机制和常数。这两种化合物对AChE和ChE均产生可逆抑制，RX 67 668对AChE的（I）50和Ki分别为2.5×10⁻⁵ M和4×10⁻⁶ M，对ChE的分别为2.0×10⁻⁵ M和8×10⁻⁷ M；RX 72 601对AChE的分别为7.9×10⁻⁸ M和3×10⁻⁹ M，对ChE的分别为3.2×10⁻⁷ M和1×10⁻⁸ M。抑制作用的动力学分析揭示了一种纯粹的竞争性机制。假定这两种酯酶的抑制是由于这两种物质带正电荷的吡咯烷部分与活性中心的阴离子亚位点结合，形成易于解离的酶-抑制剂复合物，从而损害酶-底物复合物的形成所致。