A structurally unique, potent, and selective oxytocin antagonist derived from Streptomyces silvensis.
The in vitro and in vivo oxytocin/arginine vasopressin (OT/AVP) antagonist properties of two cyclic hexapeptides derived from a newly discovered natural product (L-156,373) of Streptomyces silvensis are described. In radioligand binding assays, L-156,373 [cyclo(L-Pro-D-Phe-N-OH-L-Ile-D-piperazyl-L-piperazyl-N-Me-D -Phe)] exhibited moderate affinity for rat uterine OT receptors (Ki, 150 nM), with some selectivity (approximately 20-fold) vs. liver AVP-V1 and kidney AVP-V2 receptors. Dehydroxylation of N-hydroxyisoleucine and oxidation of the piperazic acid residues of L-156-373 produced an interesting derivative, L-365,209. These structural modifications increased OT receptor affinity and selectivity by 20- and 2.5-5-fold, respectively. In the isolated rat uterus, L-365,209 was a potent (apparent dissociation constant, 1.7 nM) and competitive OT antagonist. L-365,209 also blocked the effects of AVP at both AVP-V1 (phosphatidylinositol turnover in rat hepatocytes) and AVP-V2 (adenylate cyclase in rat kidney medulla) receptors, but only at low micromolar concentrations. L-365,209, given iv to anesthetized rats, antagonized the action of exogenous OT on the uterus (ID50, 460 micrograms/kg) with a relatively long duration of action. L-365,209 represents a unique class of compounds that provides an entirely new approach for the design of antagonists for these neurohypophyseal hormones.
Pettibone
D J
DJ
Department of New Lead Pharmacology, Merck, Sharp, and Dohme Research Laboratories, West Point, Pennsylvania 19486.
Clineschmidt
B V
BV
Anderson
P S
PS
Freidinger
R M
RM
Lundell
G F
GF
Koupal
L R
LR
Schwartz
C D
CD
Williamson
J M
JM
Goetz
M A
MA
Hensens
O D
OD
D000818:Animals; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000378:metabolism; D010121:Oxytocin / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000378:metabolism; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D013302:Streptomyces / Q000032:analysis*; D014599:Uterus / Q000378:metabolism
D010455:Peptides; D010456:Peptides, Cyclic; D011945:Receptors, Angiotensin; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; C060100:L 156373; C060102:L 365209; C060101:L 364918; D010121:Oxytocin