| Autor: |
McLeod RL; Neurobiology-Respiratory, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA. robbie.mcleod@spcorp.com , Tulshian DB, Bolser DC, Varty GB, Baptista M, Fernandez X, Parra LE, Zimmer JC, Erickson CH, Ho GD, Jia Y, Ng FW, Korfmacher W, Xu X, Veals J, Smith-Torhan A, Wainhaus S, Fawzi AB, Austin TM, van Heek M, Hey JA |
| Jazyk: |
angličtina |
| Zdroj: |
European journal of pharmacology [Eur J Pharmacol] 2010 Mar 25; Vol. 630 (1-3), pp. 112-20. Date of Electronic Publication: 2009 Dec 16. |
| DOI: |
10.1016/j.ejphar.2009.12.003 |
| Abstrakt: |
We describe the pharmacological and pharmacokinetic profiles of SCH 486757, a nociceptin/orphanin FQ peptide (NOP) receptor agonist that has recently entered human clinical trials for cough. SCH 486757 selectively binds human NOP receptor (K(i)=4.6+/-0.61nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01-1mg/kg) suppressed cough at 2, 4, and 6h post oral administration with a maximum efficacy occurring at 4h equivalent to codeine, hydrocodone, dextromethorphan and baclofen. The antitussive effects of SCH 486757 (3.0mg/kg, p.o.) was blocked by the NOP receptor antagonist J113397 (12mg/kg, i.p.) but not by naltrexone (10mg/kg, p.o.). SCH 486757 does not produce tolerance to its antitussive activity after a 5-day BID dosing regimen. After acute and chronic dosing paradigms, SCH 486757 (1mg/kg) inhibited capsaicin-evoked coughing by 46+/-9% and 40+/-11%, respectively. In a feline mechanically-evoked cough model, SCH 486757 produces a maximum inhibition of cough and expiratory abdominal electromyogram amplitude of 59 and 61%, respectively. SCH 486757 did not significantly affect inspiratory electromyogram amplitude. We examined the abuse potential of SCH 486757 (10mg/kg, p.o.) in a rat conditioned place preference procedure which is sensitive to classical drugs of abuse, such as amphetamine and morphine. SCH 486757 was without effect in this model. Finally, SCH 486757 displays a good oral pharmacokinetic profile in the guinea pig, rat and dog. We conclude that SCH 486757 has a favorable antitussive profile in preclinical animal models. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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