Synthesis and some pharmacological properties of [1-(L-2-hydroxy-3-mercaptopropanoic acid), 4-threonine]oxytocin (hydroxy [4-thr]oxytocin), a peptide with strikingly high oxytocic potency and of [1-(L-2-hydroxy-3-mercaptopropanoic acid)]oxytocin (hydroxy-oxytocin).
[1-(L-2-Hydroxy-3-mercaptopropanoic acid), 4-threonine]oxytocin (hydroxy[4-Thr]oxytocin) and [1-(l-2-hydroxy-3-mercaptopropanoic acid)]oxytocin (hydroxy-oxytocin) were synthesized by a combination of solid phase and classical methods of peptide synthesis. Protected octapeptides were synthesized by the solid-phase method and 1 + 8 couplings in solution were then employed to furnish the required key protected intermediates. Hydroxy[4-Thr]oxytocin has oxytocic potency as measured in the rat uterus suspended in a Mg2+-free solution, of about 4200 units/mg, eight times the potency of oxytocin, while its antidiuretic potency is approximately equal to that of oxytocin. It thus exhibits a significantly favorable oxytocic-antidiuretic sleectivity. Hydroxy-oxytocin has an oxytocic potency of approximatels 1300 units/mt, 2.5 times that of oxytocin. Threonine substitution in hydroxy-oxytocin has thus caused a significant enhancement in both oxytocic potency and selectivity. The enhancement in oxytocic potency of these two peptides relative to oxytocin and [4-Thr]oxytocin appears to correlate with their lipophilic characteristics, suggesting a significant role of lipophilicity in the interplay of oxytocin-like peptides with oxytocic receptors.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002855:Chromatography, Thin Layer; D004231:Diuresis / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D007774:Lactation / Q000187:drug effects; D008321:Mammary Glands, Animal / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D010120:Oxytocics / Q000138:chemical synthesis*; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011247:Pregnancy; D011422:Propionates / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects
D010120:Oxytocics; D011422:Propionates; D013438:Sulfhydryl Compounds; D010121:Oxytocin