Bradykinin agonist activity of a novel, potent oxytocin antagonist.
From a series of potent cyclic hexapeptide oxytocin (OT) antagonists, a compound that exhibited significant bradykinin (BK) agonist activity was identified. L-366,811 (cyclo[L-proline-D-tryptophan-L-isoleucine-D-pipecolic acid-L-piperazine-2-carboxylic acid-N-Me-D-phenylalanine]) stimulated phosphatidylinositol (PI) turnover in rat uterine slices in vitro (approximately EC50, 2 microM) with a maximal effect (15-fold increase over basal) greater than that obtained for either BK or OT. L-366,811 also elicited dose-related contractions of the isolated rat uterus, producing measurable effects at 100 nM. Several other equally potent OT antagonists from the cyclic hexapeptide structural class were either less potent or inactive as activators of uterine PI turnover or contractility. The stimulatory effects of L-366,811 on uterine PI turnover and contractions were blocked by BK antagonists but not by an arginine vasopressin (AVP)/OT antagonist. In radioligand binding studies, L-366,811 exhibited moderate affinity (IC50, 360 nM) for the [3H]BK binding site in rat uterus, consistent with its potency in the functional models. These results indicate that L-366,811 exhibits BK agonist activity in rat uterus in vitro.
Pettibone
D J
DJ
Department of New Lead Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Clineschmidt
B V
BV
Lis
E V
EV
Ransom
R W
RW
Totaro
J A
JA
Young
G S
GS
Bock
M G
MG
Freidinger
R M
RM
Veber
D F
DF
Williams
P D
PD
D000818:Animals; D001920:Bradykinin / Q000378:metabolism / Q000502:physiology*; D005260:Female; D007295:Inositol Phosphates / Q000378:metabolism; D010121:Oxytocin / Q000037:antagonists & inhibitors*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014316:Tritium; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D007295:Inositol Phosphates; D010456:Peptides, Cyclic; D014316:Tritium; C070670:L 366811; D010121:Oxytocin; D001920:Bradykinin