CLOZAPINE - SELECTIVE LABELING OF SITES RESEMBLING 5HT(6) SEROTONIN RECEPTORS MA

2020-03-26 13:56:10

Brain serotonin receptors clozapine

责任者: GLATT, CE;SNOWMAN, AM;SIBLEY, DR;SNYDER, SH 单位: JOHNS HOPKINS UNIV,SCH MED,DEPT NEUROSCI PHARMACOL & MOLEC SCI,BALTIMORE,MD 21205.;JOHNS HOPKINS UNIV,SCH MED,DEPT PSYCHIAT & BEHAV SCI,BALTIMORE,MD 21205.;NINCDS,EXPTL THERAPEUT BRANCH,BETHESDA,MD 20 来源出处: MOLECULAR MEDICINE, v 1, MAY 1995, p 398- 406 摘要: Background: 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 clozapines unique psychotropic effects. To identify sites with which clozapine preferentially interacts in a therapeutic setting, we have characterized dozapine binding to brain membranes. Materials and Methods: [H-3]Clozapine binding was examined in rat brain membranes as well as cloned-expressed 5-HT6 serotonin receptors. Results: [H-3]Clozapine binds with low nanomolar affinity to two distinct sires. One reflects muscarinic receptors consistent with the drugs anticholinergic actions. The drug competition profile of the second site most closely resembles 5HT(6) serotonin receptors, though serotonin itself displays low affinity. [H-3]Clozapine binding levels are similar in all brain regions examined with no concentration in the corpus striatum. Conclusions: Besides muscarinic receptors, clozapine primarily labels sites with properties resembling 5HT(6) 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. 关键词: CYCLODEXTRIN; NANOSPHERE; PHOTON SCANNING TUNNELING MICROSCOPY; SCANNING FORCE MICROSCOPY; SURFACE TOPOGRAPHY SCANNING FORCE MICROSCOPY; SURFACE TOPOGRAPHY; MOLECULAR-CLONING; FUNCTIONAL EXPRESSION; ANTIPSYCHOTIC-DRUGS; HIGH-AFFINITY; DOPAMINE RECEPTOR; RAT; LOCALIZATION; GENE; HIGH-AFFINITY; DOPAMINE RECEPTOR; RAT; LOCALIZATION; GENE; NEUROLEPTICS; NEURONS NEUROLEPTICS; NEURONS