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

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(1) = 46 +/- 061 nM) over classical opioid receptors In a guinea pig capsaicin Cough model, SCH 486757 (001-1 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 closing 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. (C) 2009 Elsevier B V All rights reserved.