CP-96,345, A NONPEPTIDE ANTAGONIST OF SUBSTANCE-P .2. ACTIONS ON SUBSTANCE-P-INDUCED HYPOTENSION AND BRONCHOCONSTRICTION, AND ON DEPRESSOR REFLEXES IN MAMMALS

In order to extend the in vivo pharmacological profile of CP-96,345 ((2S, 3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo[2.2.2]octan-3-amine dihydrochloride), a non-peptide antagonist of substance P, the compound was tested against substance P-induced effects on blood pressure in rabbits and on respiration pressure in guinea-pigs. In addition, CP-96,345, and its inactive (2R, 3R)-enantiomer, CP-96,344, were also tested in 2 models involving presumably substance P-mediated reflexes in the rat. The fall in blood pressure evoked by iv. injections of substance P in the rabbit was inhibited by 0.3-mu-mol kg-1 CP-96,345 iv. for at least 30 min, and almost abolished, for at least 2 h, by 3-mu-mol kg-1. In guinea-pigs, the bronchoconstriction induced by iv. injections of substance P, but not that in response to histamine or bradykinin, was inhibited by CP-96,345 (0.6 and 6.0-mu-mol kg-1, iv.) in a dose-dependent manner and this inhibition lasted for 40 min and 70 min, respectively. CP-96,345 (3-20-mu-mol kg-1, iv.) reduced depressor reflexes in response to stimulation of peripheral capsaicin-sensitive neurones in the rat. However, the inhibition was not dose-dependent and was also seen with the inactive enantiomer, CP-96,344. This effect can hardly be attributed to receptor-specific effects of CP-96,345 and may be related to unspecific actions such as those involved in the cardiac depression exhibited by both enantiomers. The present results show that CP-96,345 is a potent antagonist of substance P in vivo. The failure of CP-96,345 to show a specific inhibition of the depressor reflexes which are thought to be mediated by substance P released within the spinal cord requires further investigation.