title: Blonanserin extensively occupies rat dopamine D3 receptors at antipsychotic dose range.
abstract: Antagonism of the dopamine D3 receptor has been hypothesized to be beneficial for schizophrenia cognitive deficits, negative symptoms and extrapyramidal symptoms. However, recent animal and human studies have shown that most antipsychotics do not occupy D3 receptors in vivo, despite their considerable binding affinity for this receptor in vitro. In the present study, we investigated the D3 receptor binding of blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptors antagonist, in vitro and in vivo. Blonanserin showed the most potent binding affinity for human D3 receptors among the tested atypical antipsychotics (risperidone, olanzapine and aripiprazole). Our GTPγS-binding assay demonstrated that blonanserin acts as a potent full antagonist for human D3 receptors. All test-drugs exhibited antipsychotic-like efficacy in methamphetamine-induced hyperactivity in rats. Treatment with blonanserin at its effective dose blocked the binding of [(3)H]-(+)-PHNO, a D2/D3 receptor radiotracer, both in the D2 receptor-rich region (striatum) and the D3 receptor-rich region (cerebellum lobes 9 and 10). On the other hand, the occupancies of other test-drugs for D3 receptors were relatively low. In conclusion, we have shown that blonanserin, but not other tested antipsychotics, extensively occupies D3 receptors in vivo in rats.
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Baba
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: takeshi-enomoto@ds-pharma.co.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Horisawa
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Ono
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D065127:Dopamine D2 Receptor Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006948:Hyperkinesis / Q000188:drug therapy; D008297:Male; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; D050637:Receptors, Dopamine D3; D058830:Serotonin 5-HT2 Receptor Antagonists; C079310:blonanserin
keywords: Antipsychotic; D(2) receptor; D(3) receptor; Dopamine; Occupancy