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Pharmacological evaluation of analgesic effects of the cholecystokinin2 receptor antagonist Z-360 in mouse models of formalin- and cancer-induced pain.

Abstract
Z-360, a novel cholecystokinin(2) (CCK(2)) receptor antagonist, has been developed as a therapeutic drug for pancreatic cancer and showed pain relief action in phase Ib/IIa clinical trial. This study was attempted to elucidate the analgesic efficacy of Z-360 in mice. Oral administration of Z-360 (30-300 mg/kg) showed a dose-dependent inhibitory effect on the late phase of nociceptive responses to formalin. YF476, another CCK(2) receptor antagonist, was without effects at 1 and 10 mg/kg. In contrast, the CCK(1) receptor antagonist devazepide inhibited the nociceptive responses to formalin. In a mouse model of cancer pain, significant anti-allodynic effect of Z-360 was observed after single and repeated oral administration of 100 and 300 mg/kg doses. Anti-allodynic effect was also observed after repeated administration of devazepide. Combined single treatment with morphine and Z-360 caused an increase inhibition of pain-related responses in the pain models produced by formalin and cancer. Although Z-360 has lower affinity for CCK(1) receptor than for CCK(2) receptor, Z-360 exhibited an inhibitory effect on sulfated CCK-8-induced gallbladder emptying, a CCK(1) receptor-mediated effect, at a dose of 100 mg/kg. These results suggest that Z-360 inhibits inflammatory and cancer pain probably through the blockade of CCK(1) receptors. Z-360 is expected to become a useful drug for the pancreatic cancer with analgesic effects as well as the prolongation of survival.
AuthorsKoji Yoshinaga, Takayuki Horii, Hiroki Hamano, Runa Eta, Tomoko Ozaki, Yuki Orikawa, Kazuyoshi Yoshii, Yoshihiro Kawabata, Yuko Hori, Koichi Seto, Mineo Takei, Yasushi Kuraishi
JournalBiological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 33 Issue 2 Pg. 244-8 ( 2010) ISSN: 1347-5215 [Electronic] Japan
PMID20118547 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzodiazepinones
  • Receptor, Cholecystokinin B
  • Z-360
  • Formaldehyde
Topics
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
  • Benzodiazepinones (pharmacology, therapeutic use)
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Evaluation, Preclinical (methods)
  • Formaldehyde (toxicity)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Neoplasms (complications, drug therapy)
  • Pain (chemically induced, drug therapy, etiology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cholecystokinin B (antagonists & inhibitors, physiology)

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