Effect of a Novel NOP Receptor Agonist (SCH 225288) on Guinea Pig Irritant-Evoked, Feline Mechanically Induced and Canine Infectious Tracheobronchitis Cough

Abstract

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.

Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

“…57 This compound and a close analog 14 (SCH225288, Figure 1) 117 are high affinity NOP full agonists, and were extensively characterized in experimental models of cough (guinea pig capsaicin-induced cough, and cat mechanical-induced cough) and shown to be more potent than commonly used antitussives codeine and dextromethorphan. 116,117 Indeed, the natural peptide N/OFQ, given intravenously, has also been shown to inhibit cough in experimental models at doses that do not affect general activity in the animal. 118-120 Interestingly, compound 8 was also tested in the same models of experimental cough, and found to be effective, when administered i.p.…”

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 have previously proposed that selective non-peptide orally available nociceptin/orphanin FQ peptide (NOP) receptor agonists may be useful for the treatment of cough (McLeod et al, 2002, 2003, 2004, 2009). NOP is a G protein coupled receptor that has been found to share homology with classical opioid receptors, namely, μ (MOP), κ (KOP) and δ (DOP) receptors (Bunzow et al, 1994; Mollereau et al, 1994; Meunier et al, 1995; Costentin, 1995).…”

“…However, Ro-64-6198 is not likely a suitable compound to advance into a clinical proof of concept cough study as the drug is not readily orally absorbed. We recently reported on the preclinical antitussive profile of the selective NOP receptor agonist, SCH 225288 (McLeod et al, 2009). This compound is orally absorbed from the gastrointestinal tract, demonstrated antitussive properties in the guinea pig (irritant induced), and cat (mechanically-evoked) and showed a strong tendency to inhibit canine infectious tracheobronchitis cough (McLeod et al, 2009).…”

Where Are the New Cough Treatments: A Debriefing of Recent Clinical Proof-of-Concept Trials with the NOP Agonist SCH 486757

“…In addition to inhibiting chemical irritantprovoked cough in guinea pigs, nociceptin/orphanin FQ blocks cough produced by mechanical perturbation of the trachea in the cat [17] . Follow-up experiments with various nonpeptide NOP agonists supported the position that this pharmacological class of drug suppresses cough in animal models [18][19][20][21] .…”

“…There have been some efforts in the scientific community to develop 'exacerbated cough' animal models in which tussive activity is determined by challenge agents such as critic acid or capsaicin following SO 2 or cigarette smoke [28] . In 2009, we published a study on an infectious tracheobronchitis canine model of cough with the goal of utilizing it as a disease model to access novel antitussive drugs [21] . These approaches to the preclinical pharmacological study of cough are a step in the right direction (compared to historical cough models) but unfortunately they are not fully characterized, not standardized across different laboratories and their correlation with human cough is not fully understood.…”