可乐定对苯二氮受体激动剂和反相激动剂与大鼠皮层受体结合特性的影响(英文)

The effect of clonidine on the binding characteristics of benzodiazepine receptor agonist,inverse agonist and antagonist in the rat cortex

本研究旨在研讨α2受体激动剂可乐定对苯二氮Zhuo受体激动剂抗焦虑和反相激动剂致焦虑作用影响的可能的分子机理。在10nmol/L至1umol/L浓度范围内，可乐定对[^3H]氟硝安定与大鼠皮层相应受体低亲和位点结合无显著影响。但非竞争性拮抗其与高亲和位点的结合，在竞争取代实验中，激动剂安全和CL218872均表现为双位点结合的亲和力，对低亲和位点无显著影响，反相激动剂DMCM竞争结合曲线亦具有双位点结合特性，可乐定可使这种双位点结合转变成三位点结合，出现一个超高亲和位点，可乐定对拮抗剂Ro15-1788竞争结合特性无显著影响，结果提示，α2受体激动剂可乐定与受体结合可能导致与之相邻的苯二氮Zhuo受体发生构象变化，这种构象变化有利于激动剂与受体结合，而不利于反相激动剂的结合。

The purpose of this study is to explore the possible molecular basis for the regulatory effect of alpha-2 adrenoceptor agonist,clonidine on the anxiolytic or anxiogenic actions of benzodiazepine(BDZ)receptor agonist and inverse agonist.Clonidine,ranged from 10nmol/L to 1μmol/L,had no effect on the binding feature of [3H]flunitrizepam to the low affinity sites of BDZ receptor,but showed a non-competitive antagonism against the binding of [3H]flunitrizepam to the high affinity sites of BDZ receptor.In the displacement experiments,the competition curves of BDZ receptor agonists,such as diazepam and CL 218 872,modeled to two binding sites rather than one(p<0.01)or three(p<0.01)sites.The addition of clonidine significantly increased the affinity of BDZ receptor agonists to the high affinity sites without significant effect on the low affinity sites.The competition curves of inverse BDZ receptor agonist DMCM was illustrated in a biphasic way by a computer model of two sites.The addition of clonidine dramatically induced the 'two site' feature of DMCM displacing curve to a 'three site' state.A super-high affinity site appeared.Of further interest is that clonidine had no effect on the competition characteristics of BDZ receptor antagonist Ro 15-1788.Basing on our previous behavioral findings,the above results suggest that the action of clonidine at alpha-2 adrcnoccptors may lead to a conformational change of neighbouring BDZ receptor molecule,which may better fit to the binding of BDZ receptor agonist,but not to that ofBDZ receptor inverse agonist.