CP-96,345, a non-peptide antagonist of substance P: I. Effects on the actions mediated by substance P and related tachykinins on the guinea-pig ileum and rabbit jejunum.
The effects of a non-peptide antagonist of substance P, CP-96,345, were investigated, in vitro, on the guinea-pig ileum and the rabbit jejunum. Contractions of the guinea-pig ileum, induced by substance P and neurokinin A, were specifically inhibited by the racemate (+/-)CP-96,345 (pIC50 7.8 and 7.3, respectively). The inhibition by (+/-)CP-96,345 of contractions evoked by neurokinin B and by bradykinin (pIC50 6.1 and 4.9, respectively) was attributed to unspecific effects of the antagonist. The inhibition of substance P-induced contractions of the rabbit jejunum required a 10 times higher concentration of (+/-)CP-96,345 (pIC50 = 6.8) than was required with the guinea-pig ileum. The plateau phase of contraction of the guinea-pig ileum induced by high concentrations of substance P, neurokinin A or neurokinin B, which is known to be mediated through tachykinin receptors on intrinsic cholinergic neurones, was inhibited by 200 nM (+/-)CP-96,345 but not by the inactive enantiomer, CP-96,344. This indicates a specific inhibition of these neuronal tachykinin receptors by (+/-)CP-96,345. Contractions known to be mediated by the release of substance P, such as those evoked by capsaicin and by mesenteric nerve or field stimulation, were partially inhibited by (+/-)CP-96,345 at concentrations of 200 to 600 nM. Unspecific inhibitory effects of CP-96,345, in concentrations of 1 microM or higher, were observed on histamine-induced contractions, and on the cholinergic twitch response to electrical stimulation, of the guinea-pig ileum.(ABSTRACT TRUNCATED AT 250 WORDS)
Legat
F J
FJ
Institut für Experimentelle und Klinische Pharmakologie, Karl-Franzens-Universität Graz, Austria.
Griesbacher
T
T
Lembeck
F
F
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D006584:Hexamethonium Compounds / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007583:Jejunum / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010275:Parasympathetic Nervous System / Q000187:drug effects; D010528:Peristalsis / Q000187:drug effects; D011817:Rabbits; D013237:Stereoisomerism; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000502:physiology; D015320:Tachykinins / Q000494:pharmacology / Q000502:physiology*
D001713:Biphenyl Compounds; D006584:Hexamethonium Compounds; D015320:Tachykinins; D013373:Substance P; D006632:Histamine; D002211:Capsaicin; C066892:CP 96345