PMID- 9154323
OWN - NLM
STAT- MEDLINE
DCOM- 19970716
LR  - 20161124
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 121
IP  - 2
DP  - 1997 May
TI  - Central antitussive activity of the NK1 and NK2 tachykinin receptor antagonists, 
      CP-99,994 and SR 48968, in the guinea-pig and cat.
PG  - 165-70
AB  - 1. The purpose of this study was to investigate the antitussive activity and 
      sites of action of the NK1 and NK2 tachykinin receptor antagonists, CP-99,994, SR 
      48968, and the racemate of SR 48968, SR 48212A in the cat and guinea-pig. 2. 
      Guinea-pigs were dosed subcutaneously (s.c.) with CP-99,994, SR 48212A or SR 
      48968 one hour before exposure to aerosols of capsaicin (0.3 mM) to elicit 
      coughing. Coughs were detected with a microphone and counted. 3. 
      Intracerebroventricular (i.c.v.) cannulae were placed in the lateral cerebral 
      ventricles of anaesthetized guinea-pigs. Approximately one week later, the 
      animals were dosed with CP-99,994 or SR 48212A (i.c.v.) and exposed to aerosols 
      of capsaicin (0.3 mM) to elicit coughing. 4. Cough was produced in anaesthetized 
      cats by mechanical stimulation of the intrathoracic trachea and was monitored 
      from electromyograms of respiratory muscle activity. Cannulae were placed for 
      intravenous (i.v.) or, in separate groups of animals, intravertebral arterial 
      (i.a.) administration of CP-99,994, SR 48212A or SR 48968. Dose-response 
      relationships for i.v. and i.a. administration of each drug were generated to 
      determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio 
      (EDR). The EDR will be 20 or greater for a centrally active drug and less than 20 
      for a peripherally active drug. 5. In the guinea-pig, CP-99,994 (0.1-30 mg kg-1, 
      s.c.), SR 48212A (1.0-30 mg kg-1, s.c.), and SR 48968 (0.3-3.0 mg kg-1, s.c.) 
      inhibited capsaicin-induced cough in a dose-dependent manner. Capsaicin-induced 
      cough was also inhibited by i.c.v. administration of CP-99,994 (10 and 100 
      micrograms) or SR 48212A (100 micrograms). 6. In the cat, both CP-99,994 
      (0.0001-0.3 mg kg-1, i.a., n = 5; 0.003-3.0 mg kg-1, i.v., n = 5) and SR 48212A 
      (0.003-1.0 mg kg-1, i.a., n = 5; 0.01-3.0 mg kg-1, i.v., n = 5) inhibited 
      mechanically induced cough by either the i.v. or i.a. routes in a dose-dependent 
      manner. SR 48968 (0.001-0.3 mg kg-1, i.a., n = 5; 0.03-1.0 mg kg-1, i.v., n = 5) 
      inhibited cough when administered by the i.a. route in a dose-dependent manner, 
      but had no effect by the i.v. route up to a dose of 1.0 mg kg-1. Intravenous 
      antitussive potencies (ED50, 95% confidence interval (CI) of these compounds 
      were: CP-99,994 (0.082 mg kg-1, 95% CI 0.047-0.126), SR 48212A (2.3 mg kg-1, 95% 
      CI 0.5-20), and SR 48968 (> 1.0 mg kg-1, 95% CI not determined). The 
      intra-arterial potencies of these compounds were: CP-99,994 (1.0 microgram kg-1, 
      95% CI 0.4-1.8), SR 48212A (25 micrograms kg-1, 95% CI 13-52), and SR 48968 (8.0 
      micrograms kg-1, 95% CI 1-32). The derived EDRs for each compound were: 
      CP-99,994, 82; SR 48212A, 92; and SR 48968, > 125. 7. We concluded that CP-99,994 
      and SR 48968 inhibit cough in the guinea-pig and cat by a central site of action. 
      In the cat, the antitussive action of these compounds appears to be solely by a 
      central site.
FAU - Bolser, D C
AU  - Bolser DC
AD  - Department of Physiological Sciences, College of Veterinary Medicine, University 
      of Florida, Gainesville 32610-0144, USA.
FAU - DeGennaro, F C
AU  - DeGennaro FC
FAU - O'Reilly, S
AU  - O'Reilly S
FAU - McLeod, R L
AU  - McLeod RL
FAU - Hey, J A
AU  - Hey JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Antitussive Agents)
RN  - 0 (Benzamides)
RN  - 0 (Piperidines)
RN  - 136982-36-0 (3-(2-methoxybenzylamino)-2-phenylpiperidine)
RN  - 720U2QK8I5 (SR 48968)
SB  - IM
MH  - Animals
MH  - Antitussive Agents/*pharmacology
MH  - Benzamides/*pharmacology
MH  - Cats
MH  - Central Nervous System/*drug effects
MH  - Cough/*drug therapy
MH  - Dose-Response Relationship, Drug
MH  - Guinea Pigs
MH  - Piperidines/*pharmacology
PMC - PMC1564671
EDAT- 1997/05/01 00:00
MHDA- 1997/05/01 00:01
PMCR- 1998/05/01
CRDT- 1997/05/01 00:00
PHST- 1997/05/01 00:00 [pubmed]
PHST- 1997/05/01 00:01 [medline]
PHST- 1997/05/01 00:00 [entrez]
PHST- 1998/05/01 00:00 [pmc-release]
AID - 0701111 [pii]
AID - 10.1038/sj.bjp.0701111 [doi]
PST - ppublish
SO  - Br J Pharmacol. 1997 May;121(2):165-70. doi: 10.1038/sj.bjp.0701111.