Effect of a novel NOP receptor agonist (SCH 225288) on guinea pig irritant-evoked, feline mechanically induced and canine infectious tracheobronchitis cough.
BACKGROUND
Previous studies have demonstrated that nociceptin/orphanin FQ (N/OFQ), the endogenous peptide ligand for the G-protein-coupled NOP receptor, inhibits cough in experimental models. SCH 225288 is a nonpeptide, orally active NOP agonist that may provide the foundation for the development of novel treatments for cough.


METHODS
First we characterized the selectivity of SCH 225288 in human receptor binding assays. Afterwards, the antitussive activity of SCH 225288 was studied in three mechanistically distinct cough models. Specifically, we observed the cough-suppressant effect of SCH 225288 in a guinea pig capsaicin irritant-evoked cough model, a feline mechanically induced cough model and finally in a canine Bordetella bronchiseptica disease model.


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.
McLeod
Robbie L
RL
Neurobiology, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA. robbie.mcleod@spcorp.com
Tulshian
Deen B
DB
Ho
Ginny D
GD
Fernandez
Xiomara
X
Bolser
Donald C
DC
Parra
Leonard E
LE
Zimmer
Jennifer C
JC
Erickson
Christine H
CH
Fawzi
Ahmad B
AB
Jayappa
Huchappa
H
Lehr
Craig
C
Erskine
Jason
J
Smith-Torhan
April
A
Zhang
Hongtao
H
Hey
John A
JA
D000818:Animals; D000996:Antitussive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001885:Bordetella Infections / Q000188:drug therapy / Q000662:veterinary; D016950:Bordetella bronchiseptica / Q000302:isolation & purification; D016466:CHO Cells; D002211:Capsaicin; D002415:Cats; D003371:Cough / Q000188:drug therapy*; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D011957:Receptors, Opioid / Q000819:agonists*; D013045:Species Specificity; D013997:Time Factors; D014326:Tropanes / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000094942:Nociceptin Receptor
C545455:3-(2-(aminomethyl)phenyl)-8-(bis(2 chlorophenyl)methyl)-8-azabicyclo (3.2.1)octan-3-ol; D000996:Antitussive Agents; D011957:Receptors, Opioid; D014326:Tropanes; D002211:Capsaicin; D000094942:Nociceptin Receptor