title: Pharmacology of CP-99,994; a nonpeptide antagonist of the tachykinin neurokinin-1 receptor.
abstract: (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) binds selectively and with high affinity (Ki = 0.25 nM) to neurokinin (NK)-1 tachykinin receptors in a human cell line and in guinea pigs where it acts as an antagonist as evidenced by its blockade of substance P-induced excitation of locus coeruleus neurons in vitro. Subcutaneously administered CP-99,994 antagonized locomotor activity in guinea pigs induced by intraventricular infusion of [Sar9,Met(O2)11]-substance P (50 micrograms) with an ID50 = 0.59 mg/kg, indicating that CP-99,994 penetrates into the central nervous system. Orally administered CP-99,994 potently 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 microM) for the L-type calcium channel in contrast to CP-96,345 (IC50 = 27 nM) an earlier nonpeptide antagonist. Thus, CP-99,994 represents an important pharmacological tool for investigating the physiological role of substance P and a potentially novel therapeutic agent for treating a variety of diseases.
authors.affiliation: Department of Neuroscience, Pfizer, Inc., Groton, Connecticut.
authors.forename: S
authors.initials: S
authors.lastname: McLean
authors.forename: A
authors.initials: A
authors.lastname: Ganong
authors.forename: P A
authors.initials: PA
authors.lastname: Seymour
authors.forename: R M
authors.initials: RM
authors.lastname: Snider
authors.forename: M C
authors.initials: MC
authors.lastname: Desai
authors.forename: T
authors.initials: T
authors.lastname: Rosen
authors.forename: D K
authors.initials: DK
authors.lastname: Bryce
authors.forename: K P
authors.initials: KP
authors.lastname: Longo
authors.forename: L S
authors.initials: LS
authors.lastname: Reynolds
authors.forename: G
authors.initials: G
authors.lastname: Robinson
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D015220:Calcium Channels / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects* / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000187:drug effects / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000187:drug effects / Q000378:metabolism; D013045:Species Specificity; D013373:Substance P / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D002211:Capsaicin