Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain.

Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain. Research Abstract Details 

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Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain. Abstract Text:

Ryo Hirose,Haruhiko Manabe,Hiromi Nonaka,Koji Yanagawa,Kaori Akuta,Soichiro Sato,Etsuo Ohshima,Michio Ichimura,

We employed an ex vivo [(3)H]rolipram binding experiment to elucidate the mechanism of emetic activity of phosphodiesterase 4 inhibitors. In Suncus murinus (an insectivore used for evaluation of emesis), emetic potential as well as ability to occupy the high-affinity rolipram binding site in brain membrane fraction in vivo were determined for phosphodiesterase 4 inhibitors. In vitro, [(3)H]rolipram bound to the membrane fraction of S. murinus brain with high affinity and its value was comparable to that for rat brain (K(d)=3.6 nM and 3.5 nM, respectively). The test compounds included denbufylline, rolipram, piclamilast, CDP840 and KF19514, each of which possessed similar affinities for the rolipram binding sites in both S. murinus and rat brain. In S. murinus, these compounds induced emesis via intraperitoneal administration. Their ED(50) values were as follows: denbufylline (1.4 mg/kg), rolipram (0.16 mg/kg), piclamilast (1.8 mg/kg), CDP840 (20 mg/kg), and KF19514 (0.030 mg/kg). In addition, these compounds occupied the high-affinity rolipram binding site in vivo as detected by dose-dependent reduction in capacity of ex vivo [(3)H]rolipram binding in brain membrane fractions. A clear correlation was observed between dose required to induce emesis and that to occupy the high-affinity rolipram binding site for individual phosphodiesterase 4 inhibitors. We conclude that the emetic effect of phosphodiesterase 4 inhibitors is caused at least in part via binding to the high-affinity rolipram binding site in brain in vivo.

Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain. Publishing Authors By Initials

R Hirose,H Manabe,H Nonaka,K Yanagawa,K Akuta,S Sato,E Ohshima,M Ichimura,

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Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: European journal of pharmacology

VOLUME: 573

Page Numbers: 93-9

Journal Abbreviation: Eur. J. Pharmacol.

ISSN: 0014-2999

DAY: 4

MONTH: 07

YEAR: 2007

Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain. Information

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LANGUAGE: eng

NlmUniqueID: 1254354

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Grant and Affiliation Information for Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain.

AFFILIATION: Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi, Shizuoka, 411-8731, Japan.

Country: Netherlands

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MEDLINETA: Eur J Pharmacol

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