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: Ayaka Tatara, Saki Shimizu, Atsushi Masui, Miyuki Tamura, Shoko Minamimoto, Yuto Mizuguchi, Midori Ochiai, Yusuke Mizobe, Yukihiro Ohno
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 138 Pg. 14-9 (Nov 2015) ISSN: 1873-5177 [Electronic] United States
• PMID: 26363311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• AD 6048
• Antipsychotic Agents
• Oncogene Proteins v-fos
• Piperazines
• Piperidines
• Pyridines
• blonanserin
• Haloperidol
• Apomorphine

Topics

• Animals
• Antipsychotic Agents (pharmacology)
• Apomorphine (antagonists & inhibitors, pharmacology)
• Basal Ganglia Diseases (psychology)
• Behavior, Animal (drug effects)
• Catalepsy (chemically induced, psychology)
• Corpus Striatum (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Gene Expression (drug effects)
• Haloperidol (pharmacology)
• Injections, Subcutaneous
• Male
• Mice
• Nucleus Accumbens (drug effects, metabolism)
• Oncogene Proteins v-fos (biosynthesis, drug effects)
• Piperazines (pharmacokinetics, pharmacology)
• Piperidines (pharmacokinetics)
• Pyridines (pharmacology)