Modulation of the Clozapine Structure Increases Its Selectivity for the Dopamine D4 Receptor

Clozapine has a more marked affinity for the recently cloned dopamine D4 receptor than for the dopamine D2 receptor. In the search for a selective ligand for the dopamine D4 receptor, useful as a pharmacological tool or as a potent atypical antipsychotic, a pyridobenzodiazepine derivative bioisoster of clozapine, JL 18, 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido [2,3-b][1,4]benzodiazepine, was found to be the most dopamine D4-selective ligand belonging to the diarylazepine class. Indeed, JL 18 binds to the dopamine D4 receptor with affinity up to 25 times superior to that for the dopamine D2 receptor and presents reduced affinities for other receptors.