Inhibition of tachykinin-induced hypotension in dogs by CP-96,345, a selective blocker of NK-1 receptors.
The effects of substance P, neurokinin A, neurokinin B, [Sar9, Met(O2)11]-substance P, [Nle10]-neurokinin A (4-10) and senktide (succinyl-[Asp6, MePhe8]-substance P (6-11)) on blood pressure and heart rate were studied in anesthetized dogs. Dose-dependent decreases in blood pressure and increases in heart rate were caused by each peptide except senktide. The latter elicited weak hypotensive or hypertensive responses at high doses. The order or potency was as follows: [Sar9, Met(O2)11]-substance P greater than or equal to substance P greater than neurokinin A greater than neurokinin B greater than [Nle10]-neurokinin A (4-10) much greater than senktide. CP-96,345, [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine] a selective NK-1 tachykinin receptor blocker, inhibited substance P-induced hypotension in a dose-related manner. Responses to each of the other peptides were inhibited by CP-96,345, 1.0 mg/kg (excluding senktide against which CP-96,345 was not tested). CP-96,344 (1.0 mg/kg i.v.) the 2R-3R enantiomer of CP-96,345 which does not block NK-1 receptors, had no effect on substance P-induced hypotension. We conclude that tachykinin-induced hypotension in dogs is mediated by NK-1 tachykinin receptors.
Constantine
J W
JW
Exploratory Medicinal Chemistry, Pfizer Inc., Groton, CT 06340.
Lebel
W S
WS
Woody
H A
HA
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003655:Decerebrate State; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D015288:Neurokinin A / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D018039:Receptors, Tachykinin; D013237:Stereoisomerism; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D015320:Tachykinins / Q000037:antagonists & inhibitors*
D001713:Biphenyl Compounds; D010446:Peptide Fragments; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D015320:Tachykinins; C054724:senktide; C062618:substance P, Sar(9)-Met(O2)(11)-; D013373:Substance P; D015288:Neurokinin A; C056408:neurokinin A(4-10); D007545:Isoproterenol; C066892:CP 96345