title: Modulation of the clozapine structure increases its selectivity for the dopamine D4 receptor.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, University of Liège, Belgium.
authors.forename: J F
authors.initials: JF
authors.lastname: Liégeois
authors.forename: J
authors.initials: J
authors.lastname: Bruhwyler
authors.forename: J
authors.initials: J
authors.lastname: Damas
authors.forename: F
authors.initials: F
authors.lastname: Rogister
authors.forename: B
authors.initials: B
authors.lastname: Masereel
authors.forename: J
authors.initials: J
authors.lastname: Geczy
authors.forename: J
authors.initials: J
authors.lastname: Delarge
mesh_terms: D001058:Apomorphine / Q000031:analogs & derivatives / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002478:Cells, Cultured; D003024:Clozapine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D050638:Receptors, Dopamine D4; D013134:Spiperone / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C493599:DRD4 protein, human; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; C093454:JL 18; D013134:Spiperone; C009074:N-n-propylnorapomorphine; D003024:Clozapine; D001058:Apomorphine