Pharmacology of CP-99,994; a nonpeptide antagonist of the tachykinin neurokinin-1 receptor.
(+)-(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.
McLean
S
S
Department of Neuroscience, Pfizer, Inc., Groton, Connecticut.
Ganong
A
A
Seymour
P A
PA
Snider
R M
RM
Desai
M C
MC
Rosen
T
T
Bryce
D K
DK
Longo
K P
KP
Reynolds
L S
LS
Robinson
G
G
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
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