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Chlorbipram: a novel PDE4 inhibitor with improved safety as a potential antidepressant and cognitive enhancer.

Abstract
Major depressive disorder is a common, but serious, psychiatric dysfunction that affects 21% of the population worldwide. Rolipram, a first-generation phosphodiesterase-4 (PDE4) inhibitor, has been shown to have significant antidepressant and cognitive enhancement effects; however, it was unsuccessful in clinic trials because of PDE4-dependent side effects such as nausea and emesis. In this study, we investigated the neuropharmacology of the novel PDE4 inhibitor chlorbipram and the classical PDE4 inhibitor rolipram. Using antidepressant-sensitive behavioral tests, we demonstrated that the acute single administration of chlorbipram (0.075-0.6 mg/kg) produced antidepressant-like effects, as evidenced by decreases in the duration of immobility in Kunming mice in the forced swim and tail suspension tests, and no significant changes in locomotor activity. Scopolamine-induced cognitive dysfunction was also significantly attenuated in the Morris water maze test after the treatment of Sprague Dawley rats with different doses of chlorbipram (0.5-1.5mg/kg). Furthermore, we evaluated the emetic potential of chlorbipram in beagle dogs. After oral administration, 0.5mg/kg rolipram showed emetic profiles in all dogs within 20 minutes, whereas chlorbipram did not induce any emesis during the 120-min observation period, even at the 1.0mg/kg dose. Together, our data suggest that chlorbipram is a novel antidepressant and cognitive enhancer with little or no emetic potency.
AuthorsMing-Zi Zhang, Zhong-Zhen Zhou, Xin Yuan, Yu-Fang Cheng, Bing-Tian Bi, Mei-Fang Gong, Yu-Pin Chen, Jiang-Ping Xu
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 721 Issue 1-3 Pg. 56-63 (Dec 05 2013) ISSN: 1879-0712 [Electronic] Netherlands
PMID24113523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2013 Elsevier B.V. All rights reserved.
Chemical References
  • Antidepressive Agents
  • Phosphodiesterase 4 Inhibitors
  • Pyridazines
  • chlorbipram
  • pyridazine
  • Cyclic Nucleotide Phosphodiesterases, Type 4
Topics
  • Animals
  • Antidepressive Agents (adverse effects, pharmacology)
  • Behavior, Animal (drug effects)
  • Cognition (drug effects)
  • Cyclic Nucleotide Phosphodiesterases, Type 4 (metabolism)
  • Dogs
  • Female
  • Male
  • Mice
  • Phosphodiesterase 4 Inhibitors (adverse effects, pharmacology)
  • Pyridazines (adverse effects, pharmacology)
  • Rats
  • Safety
  • Vomiting (chemically induced)

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