METHODS: RESULTS:
SCH 225288 selectively binds human NOP receptor (K(i) = 0.38 +/- 0.02 nmol/l) over classical
opioid receptors (COR). In a guinea pig
capsaicin cough model,
SCH 225288 (0.1-1 mg/kg) suppressed
cough at 2, 4, and 6 h after
oral administration. The
antitussive effect of
SCH 225288 (3.0 mg/kg, p.o.) was blocked by the NOP antagonist J113397 (12 mg/kg, i.p.) but not by the classical
opioid receptor (COR) antagonist,
naltrexone (3.0 mg/kg, i.p.). In the anesthetized cat, we evaluated the effects of
SCH 225288 given either intravenously or via the intravertebral artery against the increases in
cough number and respiratory expiratory and inspiratory muscle (rectus abdominis and parasternal) electromyographic (EMG) activities due to perturbations of the intrathoracic trachea.
SCH 225288 (0.03-3.0 mg/kg, i.v.) inhibited both
cough number and abdominal EMG amplitudes. Similarly,
SCH 225288 (0.001-0.3 mg/kg) administered intra-arterially also diminished
cough number and abdominal EMG amplitudes. No significant effect of the
drug was noted on parasternal EMG activity. Finally, we studied the
antitussive actions of
SCH 225288 (1.0 mg/kg) in a canine B. bronchiseptica disease model. In this model, dogs were challenged intranasally with B. bronchiseptica. Comparisons were made between a vehicle group, an
SCH 225288 (1.0 mg/kg, p.o., q.d.) and a
butorphanol (0.6 mg/kg, p.o., b.i.d.) group on the mean change in
cough scores from baseline values and days 6-9 after B. bronchiseptica challenge.
SCH 225288 (1.0 mg/kg, p.o., q.d.) displayed a positive
antitussive tendency (p = 0.06) to inhibit B. bronchiseptica
cough whereas
butorphanol (0.6 mg/kg, p.o., b.i.d.) was devoid of
antitussive activity.
CONCLUSIONS: Taken together, the present data show that
SCH 225288 is a potent and effective
antitussive agent in animal models of
cough. Furthermore, these findings indicate that NOP agonists represent a promising new therapeutic approach for the treatment of
cough without the side effect liabilities associated with
opioid antitussives.