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

Abstract

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 ± 0.61 nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01-1 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 dosing 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.

Cough: an unmet clinical need

“…In the United States, only three non‐prescription (over‐the‐counter; OTC) agents are approved as anti‐tussives: (i) chlophedianol, a medication available for purchase only through the Internet from a limited number of suppliers, and about which no research has been published since the early 1960s; (ii) diphenhydramine, a first‐generation sedating antihistamine; and (iii) dextromethorphan (FDA, 1987, 1994). Animal studies in various species (Eddy et al ., 1969; Bolser et al ., 1993; Kotzer et al ., 2000; McLeod et al ., 2010) and studies of induced cough in humans (Bickerman et al ., 1957; Karttunen et al ., 1987; Grattan et al ., 1995; Ramsay et al ., 2008) have clearly demonstrated the anti‐tussive effect of dextromethorphan. Recently, controversy has arisen because of the dearth of adequately performed clinical trials demonstrating the efficacy of dextromethorphan in acute cough due to URI (Bolser, 2006; Dicpinigaitis et al ., 2009).…”

Targeting peripheral afferent nerve terminals for cough and dyspnea

“…GPCRs may also serve to inhibit excitability of vagal afferent nerves to decrease generator potential amplitude in response to an activating stimulus. An example of this may be found in the nociceptive receptor NOP1, as well as certain opioid and cannabinoid receptors [20] [21]. …”

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.…”