Correlation between emetic effect of phosphodiesterase 4 inhibitors and their occupation of the high-affinity rolipram binding site in Suncus murinus brain.
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.
Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi, Shizuoka, 411-8731, Japan.
Ryo
R
Hirose
Haruhiko
H
Manabe
Hiromi
H
Nonaka
Koji
K
Yanagawa
Kaori
K
Akuta
Soichiro
S
Sato
Etsuo
E
Ohshima
Michio
M
Ichimura
D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000633:toxicity; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008297:Male; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry / Q000633:toxicity; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D012788:Shrews; D014316:Tritium; D014839:Vomiting / Q000139:chemically induced*; D014970:Xanthines / Q000008:administration & dosage / Q000633:toxicity
D001549:Benzamides; C106878:KF 19514; D009287:Naphthyridines; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D014970:Xanthines; C043898:denbufylline; D014316:Tritium; C102660:CDP 840; D020889:Rolipram; C087566:piclamilast