title: Atypical antipsychotic properties of AD-6048, a primary metabolite of blonanserin.
abstract: Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin.
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Tatara
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masui
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Minamimoto
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Mizuguchi
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Ochiai
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mizobe
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. Electronic address: yohno@gly.oups.ac.jp.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ohno
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001480:Basal Ganglia Diseases / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D016761:Oncogene Proteins v-fos / Q000096:biosynthesis / Q000187:drug effects; D010879:Piperazines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010880:Piperidines / Q000493:pharmacokinetics*; D011725:Pyridines / Q000494:pharmacology*
chemical_list: C552348:AD 6048; D014150:Antipsychotic Agents; D016761:Oncogene Proteins v-fos; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; C079310:blonanserin; D006220:Haloperidol; D001058:Apomorphine
keywords: AD-6048; Antipsychotic actions; Atypical antipsychotic; Blonanserin; Extrapyramidal side effects; Schizophrenia