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 o...

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Veröffentlicht in:Pharmacology 2009-01, Vol.84 (3), p.153-161
Hauptverfasser: McLeod, Robbie L., Tulshian, Deen B., Ho, Ginny D., Fernandez, Xiomara, Bolser, Donald C., Parra, Leonard E., Zimmer, Jennifer C., Erickson, Christine H., Fawzi, Ahmad B., Jayappa, Huchappa, Lehr, Craig, Erskine, Jason, Smith-Torhan, April, Zhang, Hongtao, Hey, John A.
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container_end_page 161
container_issue 3
container_start_page 153
container_title Pharmacology
container_volume 84
creator McLeod, Robbie L.
Tulshian, Deen B.
Ho, Ginny D.
Fernandez, Xiomara
Bolser, Donald C.
Parra, Leonard E.
Zimmer, Jennifer C.
Erickson, Christine H.
Fawzi, Ahmad B.
Jayappa, Huchappa
Lehr, Craig
Erskine, Jason
Smith-Torhan, April
Zhang, Hongtao
Hey, John A.
description 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 tog
doi_str_mv 10.1159/000235601
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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.</description><identifier>ISSN: 0031-7012</identifier><identifier>EISSN: 1423-0313</identifier><identifier>DOI: 10.1159/000235601</identifier><identifier>PMID: 19696521</identifier><language>eng</language><publisher>Basel, Switzerland: S. Karger AG</publisher><subject>Animals ; Antitussive Agents - administration &amp; dosage ; Antitussive Agents - adverse effects ; Antitussive Agents - pharmacology ; Bordetella bronchiseptica - isolation &amp; purification ; Bordetella Infections - drug therapy ; Bordetella Infections - veterinary ; Capsaicin ; Cats ; CHO Cells ; Cough - drug therapy ; Cricetinae ; Cricetulus ; Disease Models, Animal ; Dogs ; Dose-Response Relationship, Drug ; Female ; Guinea Pigs ; Humans ; Male ; Original Paper ; Receptors, Opioid - agonists ; Species Specificity ; Time Factors ; Tropanes - administration &amp; dosage ; Tropanes - adverse effects ; Tropanes - pharmacology</subject><ispartof>Pharmacology, 2009-01, Vol.84 (3), p.153-161</ispartof><rights>2009 S. Karger AG, Basel</rights><rights>Copyright 2009 S. Karger AG, Basel.</rights><rights>Copyright (c) 2009 S. Karger AG, Basel</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c361t-f43f222e4b2d0baabd84397ab0775c703b369ef5121dc73c861459dbacdc3ab03</citedby><cites>FETCH-LOGICAL-c361t-f43f222e4b2d0baabd84397ab0775c703b369ef5121dc73c861459dbacdc3ab03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,2423,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19696521$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McLeod, Robbie L.</creatorcontrib><creatorcontrib>Tulshian, Deen B.</creatorcontrib><creatorcontrib>Ho, Ginny D.</creatorcontrib><creatorcontrib>Fernandez, Xiomara</creatorcontrib><creatorcontrib>Bolser, Donald C.</creatorcontrib><creatorcontrib>Parra, Leonard E.</creatorcontrib><creatorcontrib>Zimmer, Jennifer C.</creatorcontrib><creatorcontrib>Erickson, Christine H.</creatorcontrib><creatorcontrib>Fawzi, Ahmad B.</creatorcontrib><creatorcontrib>Jayappa, Huchappa</creatorcontrib><creatorcontrib>Lehr, Craig</creatorcontrib><creatorcontrib>Erskine, Jason</creatorcontrib><creatorcontrib>Smith-Torhan, April</creatorcontrib><creatorcontrib>Zhang, Hongtao</creatorcontrib><creatorcontrib>Hey, John A.</creatorcontrib><title>Effect of a Novel NOP Receptor Agonist (SCH 225288) on Guinea Pig Irritant-Evoked, Feline Mechanically Induced and Canine Infectious Tracheobronchitis Cough</title><title>Pharmacology</title><addtitle>Pharmacology</addtitle><description>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.</description><subject>Animals</subject><subject>Antitussive Agents - administration &amp; dosage</subject><subject>Antitussive Agents - adverse effects</subject><subject>Antitussive Agents - pharmacology</subject><subject>Bordetella bronchiseptica - isolation &amp; purification</subject><subject>Bordetella Infections - drug therapy</subject><subject>Bordetella Infections - veterinary</subject><subject>Capsaicin</subject><subject>Cats</subject><subject>CHO Cells</subject><subject>Cough - drug therapy</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Disease Models, Animal</subject><subject>Dogs</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Guinea Pigs</subject><subject>Humans</subject><subject>Male</subject><subject>Original Paper</subject><subject>Receptors, Opioid - agonists</subject><subject>Species Specificity</subject><subject>Time Factors</subject><subject>Tropanes - administration &amp; dosage</subject><subject>Tropanes - adverse effects</subject><subject>Tropanes - pharmacology</subject><issn>0031-7012</issn><issn>1423-0313</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpt0ctO3DAUBmCroioD7YI9QkfqpkiE-pLEyXIUDcxIXEYtXUeOLzOGYA92gsS78LAYzQg2XR3J59P_Sz4IHRF8TkhR_8YYU1aUmHxBE5JTlmFG2B6a4DQzjgndRwcx3idWUl59Q_ukLuuyoGSCXmfGaDmANyDgxj_rHm5ul_BHS70ZfIDpyjsbB_j1t5kDpQWtqlPwDi5H67SApV3BIgQ7CDdks2f_oNUZXOg-LeFay7VwVoq-f4GFU6PUCoRT0KTXtF-492brxwh3Qci19l3wTq7tYCM0flytv6OvRvRR_9jNQ_TvYnbXzLOr28tFM73KJCvJkJmcGUqpzjuqcCdEp6qc1Vx0mPNCcsw6VtbaFIQSJTmTVUnyoladkEqypNgh-rnN3QT_NOo4tPd-DC5VtgSXNeM5r_OkTrdKBh9j0KbdBPsowktC7fsd2o87JHuySxy7R60-5e7jPysfRFjp8AGW8-k2ot0ok9Txf9Wu5Q1x75YQ</recordid><startdate>20090101</startdate><enddate>20090101</enddate><creator>McLeod, Robbie L.</creator><creator>Tulshian, Deen B.</creator><creator>Ho, Ginny D.</creator><creator>Fernandez, Xiomara</creator><creator>Bolser, Donald C.</creator><creator>Parra, Leonard E.</creator><creator>Zimmer, Jennifer C.</creator><creator>Erickson, Christine H.</creator><creator>Fawzi, Ahmad B.</creator><creator>Jayappa, Huchappa</creator><creator>Lehr, Craig</creator><creator>Erskine, Jason</creator><creator>Smith-Torhan, April</creator><creator>Zhang, Hongtao</creator><creator>Hey, John A.</creator><general>S. 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Parra, Leonard E. ; Zimmer, Jennifer C. ; Erickson, Christine H. ; Fawzi, Ahmad B. ; Jayappa, Huchappa ; Lehr, Craig ; Erskine, Jason ; Smith-Torhan, April ; Zhang, Hongtao ; Hey, John A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c361t-f43f222e4b2d0baabd84397ab0775c703b369ef5121dc73c861459dbacdc3ab03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Antitussive Agents - administration &amp; dosage</topic><topic>Antitussive Agents - adverse effects</topic><topic>Antitussive Agents - pharmacology</topic><topic>Bordetella bronchiseptica - isolation &amp; purification</topic><topic>Bordetella Infections - drug therapy</topic><topic>Bordetella Infections - veterinary</topic><topic>Capsaicin</topic><topic>Cats</topic><topic>CHO Cells</topic><topic>Cough - drug therapy</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Disease Models, Animal</topic><topic>Dogs</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Guinea Pigs</topic><topic>Humans</topic><topic>Male</topic><topic>Original Paper</topic><topic>Receptors, Opioid - agonists</topic><topic>Species Specificity</topic><topic>Time Factors</topic><topic>Tropanes - administration &amp; dosage</topic><topic>Tropanes - adverse effects</topic><topic>Tropanes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McLeod, Robbie L.</creatorcontrib><creatorcontrib>Tulshian, Deen B.</creatorcontrib><creatorcontrib>Ho, Ginny D.</creatorcontrib><creatorcontrib>Fernandez, Xiomara</creatorcontrib><creatorcontrib>Bolser, Donald C.</creatorcontrib><creatorcontrib>Parra, Leonard E.</creatorcontrib><creatorcontrib>Zimmer, Jennifer C.</creatorcontrib><creatorcontrib>Erickson, Christine H.</creatorcontrib><creatorcontrib>Fawzi, Ahmad B.</creatorcontrib><creatorcontrib>Jayappa, Huchappa</creatorcontrib><creatorcontrib>Lehr, Craig</creatorcontrib><creatorcontrib>Erskine, Jason</creatorcontrib><creatorcontrib>Smith-Torhan, April</creatorcontrib><creatorcontrib>Zhang, Hongtao</creatorcontrib><creatorcontrib>Hey, John A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing &amp; 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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.</abstract><cop>Basel, Switzerland</cop><pub>S. Karger AG</pub><pmid>19696521</pmid><doi>10.1159/000235601</doi><tpages>9</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0031-7012
ispartof Pharmacology, 2009-01, Vol.84 (3), p.153-161
issn 0031-7012
1423-0313
language eng
recordid cdi_crossref_primary_10_1159_000235601
source Karger Journals; MEDLINE; Alma/SFX Local Collection
subjects Animals
Antitussive Agents - administration & dosage
Antitussive Agents - adverse effects
Antitussive Agents - pharmacology
Bordetella bronchiseptica - isolation & purification
Bordetella Infections - drug therapy
Bordetella Infections - veterinary
Capsaicin
Cats
CHO Cells
Cough - drug therapy
Cricetinae
Cricetulus
Disease Models, Animal
Dogs
Dose-Response Relationship, Drug
Female
Guinea Pigs
Humans
Male
Original Paper
Receptors, Opioid - agonists
Species Specificity
Time Factors
Tropanes - administration & dosage
Tropanes - adverse effects
Tropanes - pharmacology
title Effect of a Novel NOP Receptor Agonist (SCH 225288) on Guinea Pig Irritant-Evoked, Feline Mechanically Induced and Canine Infectious Tracheobronchitis Cough
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