Glatt C E, Snowman A M, Sibley D R, Snyder S H
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Mol Med. 1995 May;1(4):398-406.
Clozapine, the classic atypical neuroleptic, exerts therapeutic actions in schizophrenic patients unresponsive to most neuroleptics. Clozapine interacts with numerous neurotransmitter receptors, and selective actions at novel subtypes of dopamine and serotonin receptors have been proposed to explain clozapine's unique psychotropic effects. To identify sites with which clozapine preferentially interacts in a therapeutic setting, we have characterized clozapine binding to brain membranes.
[3H]Clozapine binding was examined in rat brain membranes as well as cloned-expressed 5-HT6 serotonin receptors.
[3H]Clozapine binds with low nanomolar affinity to two distinct sites. One reflects muscarinic receptors consistent with the drug's anticholinergic actions. The drug competition profile of the second site most closely resembles 5HT6 serotonin receptors, though serotonin itself displays low affinity. [3H]Clozapine binding levels are similar in all brain regions examined with no concentration in the corpus striatum.
Besides muscarinic receptors, clozapine primarily labels sites with properties resembling 5HT6 serotonin receptors. If this is also the site with which clozapine principally interacts in intact human brain, it may account for the unique beneficial actions of clozapine and other atypical neuroleptics, and provide a molecular target for developing new, safer, and more effective agents.
氯氮平作为经典的非典型抗精神病药物，对大多数抗精神病药物无反应的精神分裂症患者具有治疗作用。氯氮平与多种神经递质受体相互作用，有人提出其对多巴胺和5-羟色胺受体新亚型的选择性作用可解释氯氮平独特的精神otropic效应。为了确定氯氮平在治疗环境中优先相互作用的位点，我们对氯氮平与脑膜的结合进行了表征。
在大鼠脑膜以及克隆表达的5-HT6 5-羟色胺受体中检测了[3H]氯氮平的结合。
[3H]氯氮平以低纳摩尔亲和力与两个不同位点结合。一个反映了与该药物抗胆碱能作用一致的毒蕈碱受体。第二个位点的药物竞争谱与5HT6 5-羟色胺受体最为相似，尽管5-羟色胺本身显示出低亲和力。在所检查的所有脑区中，[3H]氯氮平的结合水平相似，纹状体中无浓度差异。
除了毒蕈碱受体外，氯氮平主要标记具有类似于5HT6 5-羟色胺受体特性的位点。如果这也是氯氮平在完整人脑中主要相互作用的位点，那么它可能解释氯氮平及其他非典型抗精神病药物的独特有益作用，并为开发新的、更安全、更有效的药物提供分子靶点。
