Affinity of 10-(4-Methylpiperazino)dibenzoxepins for Clozapine and Spiroperidol Binding Sites in Rat Brain

Article abstract of DOI:10.1021/jm00349a018

10-(4-Methylpiperazino)dibenzoxepins were prepared and evaluated as potential antipsychotic agents using specific clozapine <8-chloro-11-(4-methylpiperazino)-5H-dibenzo<1,4>diazepine> binding sites in rat forebrain that are noncholinergic and nondopaminergic in nature and from which <3H>clozapine is displaced by known antipsychotic agents. <3H>Clozapine binding in the presence of atropine represents nonmuscarinic binding, while binding in the absence of atropine represents muscarinic (cholinergic) plus nonmuscarinic binding.The relative affinity for dopamine binding sites was determined by displacement of <3H>spiroperidol from binding sites in rat caudate nuclei.Thus, clozapine, its 2-chloro isomer, its dechloro analogue, and their 5H-dibenzocycloheptene and dibenzoxepin analogues have about the same relative affinity for the nonmuscarinic clozapine binding sites.At the spiroperidol (dopaminergic) sites, both the nature of the tricyclic system and the presence of chlorine atom on the tricyclic system have a substantial effect on the binding affinity.Within each series, shift of a chlorine atom from the position distal to the piperazino group to the proximal position increases the binding affinity by a factor of about nine, but removal of the chlorine atom substantially decreases the binding affinity.Nevertheless, 10-(4-methylpiperazino)dibenzoxepin has a threefold greater affinity for the dopaminergic binding sites than does clozapine itself.