Analysis of a nonpeptide antagonist for substance P on myenteric neurons of guinea-pig small intestine.

CP-96,345 [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]- 1-azabicyclo[2.2.2.]octan-3-amine], a novel nonpeptide antagonist of the substance P receptor, was evaluated for blocking action at substance P receptors on myenteric neurons of guinea-pig small intestine. Intracellular electrophysiological recording was used to determine actions of the drug on excitatory responses to substance P, on slow and fast excitatory postsynaptic potentials and action potential initiation and propagation in the neurons. CP-96,345 suppressed responses to substance P. It also suppressed spike initiation and propagation in the neuronal processes, as well as in the somal membranes. The effects of the drug on substance P responses could not be attributed to an action at substance P receptors. The mechanism of action appeared to be a nonselective local anesthetic effect on initiation and propagation of action potentials.