[Synthesis and in vitro receptor analysis of new potential oxytocin antagonists].
Oxytocin (OT) itself and the sensitivity of the uterus to OT play a crucial role in the initiation of both normal and pathologically early delivery. It recognition of the complex mechanism of action suggests that specific OT antagonists are of therapeutic value in postponing early contractions. In this study neurohypophyseal hormone analogues containing Sar in position 7, Arg in position 8, and various conformationally restricted or bulky derivatives of phenilalanine and tryptophan amino acids in position 2 were prepared to design more potent and selective OT antagonists. We determined the ligand-receptor binding characteristics of these newly synthetized peptides in the presence of [3H]oxytocin and [3H]vasopressin on isolated guinea-pig uterus, rat liver and kidney inner medulla plasma membranes. In the case of each peptides we calculated the Ki values and the selectivity ratio. The binding to the OT receptor was dramatically decreased for the Trp-derivatives containing analogues, while the Phe-derivatives containing analogues displayed a relatively high receptor affinity and have a relatively high OT/VP1 receptor selectivity.
Havass
J
J
Szegedi Tudományegyetem, Gyógyszerhatástani és Biofarmáciai Intézet, Szeged.
Bakos
K
K
Tóth
G
G
Fülöp
F
F
Falkay
G
G
D019943:Amino Acid Substitution; D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D007679:Kidney Medulla / Q000502:physiology; D008099:Liver / Q000502:physiology; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010904:Pituitary Gland, Posterior / Q000502:physiology; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000502:physiology; D014599:Uterus / Q000502:physiology; D014667:Vasopressins / Q000378:metabolism
D018045:Receptors, Oxytocin; D014667:Vasopressins; D010121:Oxytocin