Noncompetitive nature of oxytocin antagonists with general structure Mpa(1)Xxx(2)Sar(7)Arg(8).
Eight oxytocin (OT) antagonists with general structure Mpa(1)Sar(7)Arg(8), substituted at position 2 with conformationally constrained and bulky amino acids, were synthesized and pharmacologically tested. Binding affinities and selectivities of compounds for OT, and vasopressin receptor subtypes were investigated. In vitro effects of antagonists were evaluated via inhibition of OT-induced contractions of isolated guinea-pig uterus. The abilities of OT antagonists to inhibit spontaneous contractility in 24 h postpartum rat uterus were investigated. These peptides exhibited pseudoirreversible pharmacological properties, and comprise a novel group of OT antagonists for potential clinical use. Their noncompetitive pharmacological nature can be of therapeutic benefit through a sustained effect on myometrium.
Havass
J
J
Department of Pharmacodynamics and Biopharmacy, University of Szeged, P.O. Box 121, Eötvös u. 6, H-6720 Szeged, Hungary.
Bakos
K
K
Márki
A
A
Gáspár
R
R
Gera
L
L
Stewart
J M
JM
Fülöp
F
F
Tóth
G K
GK
Zupkó
I
I
Falkay
G
G
D000818:Animals; D005260:Female; D006168:Guinea Pigs; D006727:Hormone Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D007752:Obstetric Labor, Premature / Q000517:prevention & control; D010121:Oxytocin / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018045:Receptors, Oxytocin / Q000378:metabolism*; D015149:Tocolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014599:Uterus / Q000378:metabolism
D006727:Hormone Antagonists; D018045:Receptors, Oxytocin; D015149:Tocolytic Agents; D010121:Oxytocin