Neurobiology-Respiratory, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA.
Eur J Pharmacol. 2010 Mar 25;630(1-3):112-20. doi: 10.1016/j.ejphar.2009.12.003. Epub 2009 Dec 16.
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.
我们描述了 SCH 486757 的药理学和药代动力学特征，SCH 486757 是一种孤啡肽/FQ 肽（NOP）受体激动剂，最近已进入人类临床试验用于治疗咳嗽。SCH 486757 选择性地结合人 NOP 受体（K(i)=4.6+/-0.61nM），而非经典阿片受体。在豚鼠辣椒素咳嗽模型中，SCH 486757（0.01-1mg/kg）在口服后 2、4 和 6 小时抑制咳嗽，最大疗效出现在 4 小时等效于可待因、氢可酮、右美沙芬和巴氯芬。SCH 486757（3.0mg/kg，po）的镇咳作用被 NOP 受体拮抗剂 J113397（12mg/kg，ip）阻断，但不被纳洛酮（10mg/kg，po）阻断。SCH 486757 在 5 天 BID 给药方案后不会对其镇咳活性产生耐受性。在急性和慢性给药方案后，SCH 486757（1mg/kg）分别抑制 46+/-9%和 40+/-11%的辣椒素诱发咳嗽。在猫机械诱发咳嗽模型中，SCH 486757 分别产生 59%和 61%的最大咳嗽和呼气腹肌电图幅度抑制。SCH 486757 对吸气肌电图幅度没有显著影响。我们在大鼠条件性位置偏爱程序中检查了 SCH 486757（10mg/kg，po）的滥用潜力，该程序对经典滥用药物如安非他命和吗啡敏感。SCH 486757 在该模型中没有效果。最后，SCH 486757 在豚鼠、大鼠和狗中显示出良好的口服药代动力学特征。我们得出结论，SCH 486757 在临床前动物模型中具有良好的镇咳作用。
