A Potent Nonpeptide Antagonist of the Substance P (NK$_1$) Receptor

CP-96,345 [(2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2] octan-3-amine] is a potent nonpeptide antagonist of the substance P (NK$_1$) receptor. CP-96,345 inhibited $^3$H-labeled substance P binding and was a classical competitive antagonist in the NK$_1$ monoreceptor dog carotid artery preparation. CP-96,345 inhibited substance P-induced salivation in the rat, a classical in vivo bioassay, but did not inhibit NK$_2$, NK$_3$, or numerous other receptors; it is thus a selective NK$_1$ antagonist. This compound may prove to be a powerful tool for investigation of the physiological properties of substance P and exploration of its role in diseases.