Pharmacological profile of the NOP agonist and cough suppressing agent SCH 486757 (8-[Bis(2-Chlorophenyl)Methyl]-3-(2-Pyrimidinyl)-8-Azabicyclo[3.2.1]Octan-3-Ol) in preclinical models

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• 作者：Robbie L. McLeod ; Deen B. Tulshian ; Donald C. Bolser ; Geoffrey B. Varty ; Marco Baptista ; Xiomara Fern ; ez ; Leonard E. Parra ; Jennifer C. Zimmer ; Christine H. Erickson ; Ginny D. Ho ; Yanlin Jia ; Fay W. Ng ; Walter Korfmacher ; Xiaoying Xu ; John Veals ; April Smith-Torhan ; Samuel Wainhaus ; Ahmad B. Fawzi
• 关键词：Cough ; NOP receptor ; Nociceptin/orphanin FQ ; SCH 486757 ; Antitussive
• 刊名：European Journal of Pharmacology
• 出版年：2010
• 出版时间：25 March 2010
• 年：2010
• 卷：630
• 期：1-3
• 页码：112-120
• 全文大小：942 K

文摘

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 ± 0.61 nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01–1 mg/kg) suppressed cough at 2, 4, and 6 h post oral administration with a maximum efficacy occurring at 4 h equivalent to codeine, hydrocodone, dextromethorphan and baclofen. The antitussive effects of SCH 486757 (3.0 mg/kg, p.o.) was blocked by the NOP receptor antagonist J113397 (12 mg/kg, i.p.) but not by naltrexone (10 mg/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 (1 mg/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 (10 mg/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.