title: 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+/-0.61nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01-1mg/kg) suppressed cough at 2, 4, and 6h post oral administration with a maximum efficacy occurring at 4h equivalent to codeine, hydrocodone, dextromethorphan and baclofen. The antitussive effects of SCH 486757 (3.0mg/kg, p.o.) was blocked by the NOP receptor antagonist J113397 (12mg/kg, i.p.) but not by naltrexone (10mg/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 (1mg/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 (10mg/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.
authors.affiliation: Neurobiology-Respiratory, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA. robbie.mcleod@spcorp.com <robbie.mcleod@spcorp.com>
authors.forename: Robbie L
authors.initials: RL
authors.lastname: McLeod
authors.forename: Deen B
authors.initials: DB
authors.lastname: Tulshian
authors.forename: Donald C
authors.initials: DC
authors.lastname: Bolser
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: Varty
authors.forename: Marco
authors.initials: M
authors.lastname: Baptista
authors.forename: Xiomara
authors.initials: X
authors.lastname: Fernandez
authors.forename: Leonard E
authors.initials: LE
authors.lastname: Parra
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Zimmer
authors.forename: Christine H
authors.initials: CH
authors.lastname: Erickson
authors.forename: Ginny D
authors.initials: GD
authors.lastname: Ho
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Jia
authors.forename: Fay W
authors.initials: FW
authors.lastname: Ng
authors.forename: Walter
authors.initials: W
authors.lastname: Korfmacher
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Xu
authors.forename: John
authors.initials: J
authors.lastname: Veals
authors.forename: April
authors.initials: A
authors.lastname: Smith-Torhan
authors.forename: Samuel
authors.initials: S
authors.lastname: Wainhaus
authors.forename: Ahmad B
authors.initials: AB
authors.lastname: Fawzi
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Austin
authors.forename: Margaret
authors.initials: M
authors.lastname: van Heek
authors.forename: John A
authors.initials: JA
authors.lastname: Hey
mesh_terms: D000818:Animals; D000996:Antitussive Agents / Q000627:therapeutic use*; D053961:Azabicyclo Compounds / Q000494:pharmacology; D002415:Cats; D003371:Cough / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D000094942:Nociceptin Receptor
chemical_list: C549545:8-(bis(2-chlorophenyl)methyl)-3-(2-pyrimidinyl)-8-azabicyclo(3.2.1)octan-3-ol; D000996:Antitussive Agents; D053961:Azabicyclo Compounds; D011743:Pyrimidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor