Antitussive profile of the NOP agonist Ro-64-6198 in the guinea pig.

Abstract

We have previously shown that N/OFQ, the endogenous peptide ligand for the 'opioid-like' NOP receptor, inhibits cough in guinea pigs and cats. In the present study we sought to continue our characterization of the cough-suppressant effects of NOP stimulation by profiling the pulmonary and antitussive effects of a novel non-peptide NOP agonist, Ro-64-6198, in guinea pigs. In receptor-binding assays, we confirmed that Ro-64-6198 selectively binds to NOP receptors over other opioid receptors. The Ki values for Ro-64-6198 at NOP, MOP, KOP and DOP receptors was 0.3, 36, 214 and 3,787 nmol/l, respectively. In GTPgammaS-binding assays, Ro-64-6198 displayed >900-fold functional selectivity at NOP relative to MOP receptors. We evaluated the effects of Ro-64-6198 (3 and 10 micromol/l) in isolated guinea pig nodose ganglia cells on the increases in intracellular Ca2+ concentration evoked by capsaicin stimulation (1 x 10(-8)-1 x 10(-6) mol/l). Similar to previously reported data with N/OFQ, Ro-64-6198 (3 and 10 micromol/l) significantly attenuated Ca2+ responses in nodose ganglia cells produced by exposure to capsaicin. The effect of Ro-64-6198 (3 micromol/l) on capsaicin-induced intracellular Ca2+ responses was blocked by the NOP antagonist, J113397 (3 micromol/l). In guinea pig in vivo studies, aerosolized capsaicin (10-300 micromol/l) produced a dose-dependent increase in cough number. Ro-64-6198 given i.p. significantly inhibited cough due to capsaicin (300 micromol/l) exposure. In a duration study we found that the maximum antitussive effect (42 +/- 8% inhibition) of Ro-64-6198 (3 mg/kg) was observed at 1 h after i.p. administration. Also at 1 h after administration, Ro-64-6198 (0.003-3.0 mg/kg, i.p.) produced a dose-dependent inhibition of cough. The antitussive effect of Ro-64-6198 (3 mg/kg, i.p.) was blocked by J113397 (12 mg/kg, i.p.) but not by the classical opioid antagonist naltrexone (10 mg/kg, i.p.). Although the antitussive action of Ro-64-6198 may be mediated by a central and/or a peripheral site of action, we hypothesize that selective oral NOP agonists that do not penetrate the blood-brain barrier may provide a novel approach for the treatment of cough. Moreover, because these drugs do not interact at MOP receptors, they may be devoid of codeine-like side effects such as respiratory depression, sedation, constipation or proclivities for addictive liabilities.

• Authors: Robbie L McLeod, Yanlin Jia, Xiomara Fernandez, Leonard E Parra, Xin Wang, Deen B Tulshian, Eugenia J Kiselgof, Zheng Tan, Ahmad B Fawzi, April Smith-Torhan, Hongtao Zhang, John A Hey
• Journal: Pharmacology (Pharmacology) Vol. 71 Issue 3 Pg. 143-9 (Jul 2004) ISSN: 0031-7012 [Print] Switzerland
• PMID: 15161996 (Publication Type: Journal Article)
• Copyright: Copyright 2004 S. Karger AG, Basel

Chemical References

• Aerosols
• Antitussive Agents
• Imidazoles
• Receptors, Opioid
• Ro 64-6198
• Spiro Compounds
• Guanosine 5'-O-(3-Thiotriphosphate)
• Capsaicin
• Calcium
• Nociceptin Receptor

Topics

• Aerosols
• Animals
• Antitussive Agents (administration & dosage, pharmacology)
• CHO Cells
• Calcium (metabolism)
• Capsaicin (administration & dosage, pharmacology)
• Cough (prevention & control)
• Cricetinae
• Cricetulus
• Dose-Response Relationship, Drug
• Guanosine 5'-O-(3-Thiotriphosphate) (metabolism)
• Guinea Pigs
• Imidazoles (administration & dosage, pharmacology)
• In Vitro Techniques
• Injections, Intraperitoneal
• Male
• Nodose Ganglion (cytology, metabolism)
• Receptors, Opioid (agonists, metabolism)
• Spiro Compounds (administration & dosage, pharmacology)
• Nociceptin Receptor