In vitro pharmacological profile of a novel structural class of oxytocin antagonists.
A number of structurally novel cyclic hexapeptides have been characterized as potent and selective oxytocin (OT) antagonists in vitro. As a representative of this class of compounds, L-366,948 [[cyclo(L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl- L-pipecolyl-D- histidyl)]] exhibited a high binding affinity (Ki, low nanomolar) for OT receptors in rat (uterus and mammary) and primate (pregnant rhesus and human myometrium) tissue with a several hundred-fold binding selectivity vs. rat arginine vasopressin (AVP)-V1 (liver) and AVP-V2 (kidney medulla) receptors. In functional assays, L-366,948 was a pure OT antagonist, blocking both OT-stimulated contraction of the isolated rat uterus (pA2, 8.5) and phosphatidylinositol turnover in uterine slices (IC50, 40 vs. 3 nM OT), with no evidence of partial agonist activity. L-366,948 was comparatively weak as an antagonist of AVP-induced contraction of the isolated rat tail artery (AVP-V1 receptor) and AVP-stimulated adenylate cyclase (AVP-V2 receptor) activity in rat kidney medulla and did not influence prostaglandin F2 alpha- or bradykinin-induced contractions of the isolated rat uterus. L-366,948 and related compounds described in this report represent new experimental tools for the study of the pharmacology and physiology of OT.
Pettibone
D J
DJ
Department of New Lead Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania.
Clineschmidt
B V
BV
Lis
E V
EV
Reiss
D R
DR
Totaro
J A
JA
Woyden
C J
CJ
Bock
M G
MG
Freidinger
R M
RM
Tung
R D
RD
Veber
D F
DF
D000595:Amino Acid Sequence; D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors; D005260:Female; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D010121:Oxytocin / Q000037:antagonists & inhibitors*; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014316:Tritium; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects
D010456:Peptides, Cyclic; D014316:Tritium; D001127:Arginine Vasopressin; C060102:L 365209; C066874:L 366682; C066873:L 366948; D010121:Oxytocin