Effect of CP-96,345, a nonpeptide substance P receptor antagonist, on salivation in rats.
CP-96,345 [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl) methyl]-1-azabicyclo[2.2.2]octan-3-amine) antagonism of substance P-stimulated salivation was investigated in pentobarbital-anesthetized rats. Administered either intraperitoneally or orally, CP-96,345 produced dose-dependent inhibition of the sialogogic response elicited by substance P, with a median effective dose of 12-24 mumol/kg (5-10 mg/kg) of body weight, but had no effect on acetylcholine-stimulated salivation. CP-96,345 produced concentration-dependent inhibition of [3H]substance P binding to rat submaxillary gland membranes, with a median effective concentration of 34 +/- 3.6 nM. These biological activities were confined to CP-96,345 in that the 2R,3R enantiomer (CP-96,344) was without effect.
Snider
R M
RM
Department of Exploratory Medicinal Chemistry, Pfizer, Inc., Groton, CT 06340.
Longo
K P
KP
Drozda
S E
SE
Lowe
J A
JA
Leeman
S E
SE
D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D010306:Parotid Gland / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D012463:Saliva / Q000187:drug effects / Q000378:metabolism*; D013363:Submandibular Gland / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology*
D001713:Biphenyl Compounds; D018040:Receptors, Neurokinin-1; D017981:Receptors, Neurotransmitter; D013373:Substance P; C066892:CP 96345