PHARMACOLOGY OF CP-99,994 - A NONPEPTIDE ANTAGONIST OF THE TACHYKININNEUROKININ-1 RECEPTOR

2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) binds s electively and with high affinity (K(i) = 0.25 nM) to neurokinin (NK)- 1 tachykinin receptors in a human cell line and in guinea pigs where i t acts as an antagonist as evidenced by its blockade of substance P-in duced excitation of locus coeruleus neurons in vitro. Subcutaneously a dministered CP-99,994 antagonized locomotor activity in guinea pigs in duced by intraventricular infusion of [Sar-9,Met(O2)11]-substance P (5 0 mug) with an ID50 = 0.59 mg/kg, indicating that CP-99,994 penetrates into the central nervous system. Orally administered CP-99,994 potent ly blocked (ID50 = 4 mg/kg) the leakage of Evans blue dye into trachea and bronchi elicited by exposure of guinea pigs to aerosol capsaicin (1 mM). CP-99,994 has reduced affinity (IC50 = 3 muM) for the L-type c alcium channel in contrast to CP-96,345 (IC50 = 27 nM) an earlier nonp eptide antagonist. Thus, CP-99,994 represents an important pharmacolog ical tool for investigating the physiological role of substance P and a potentially novel therapeutic agent for treating a variety of diseas es.