Design of novel bicyclic analogues derived from a potent oxytocin antagonist.
Eleven new analogues were synthesized by modification of the potent oxytocin antagonist (OTA) [(S)Pmp(1), D-Trp(2), Pen(6), Arg(8)]-Oxytocin, or PA (parent antagonist), in which (S)Pmp = beta,beta-(3-thiapentamethylene)-beta-mercapto-propionic acid. By internal acylation of Lys, Orn, L-1,4-diaminobutyric acid (Dab), L-1,3-diaminopropionic acid (Dap) at position 4 with the C-terminal Gly of the peptide tail, we prepared cyclo-(4-9)-[Lys(4), Gly(9)]-PA (pA(2) = 8.77 +/- 0.27), 1, and cyclo-(4-9)-[Orn(4), Gly(9)]-PA (pA(2) = 8.81 +/- 0.25), 3, which are equipotent with PA (pA(2) = 8.68 +/- 0.18) in the rat uterotonic assay and cyclo-(4-9)-[Dab(4), Gly(9)]-PA, 4, cyclo-(4-9)-[Dap(4), Gly(9)]-PA, 5, and cyclo-(4-9)-[Pmp(1), Lys(4), Gly(9)]-PA, 2, which were weaker OTAs. Neither 1 nor 3 had activity as agonists or antagonists in the antidiuretic assay. In the pressor assay, both analogues 1 and 3, with pA(2) = 7.05 +/- 0.10 and pA(2) = 6.77 +/- 0.12, respectively, are somewhat weaker antagonists than PA (pA(2) = 7.47 +/- 0.35) showing significant gain in specificity. The [desamido(9)] PA-ethylenediamine monoamide, 6, and the dimer ([desamido(9)]-PA)(2) ethylenediamine diamide, 7, had lower potency in the uterotonic assay than PA. Additionally, we synthesized cyclo-(1-5)-[(HN)Pmp(1), Asp(5)]-PA, 8, inactive in all tests, which suggests that the intact Asn(5) side chain may be critical in the interaction of the OTAs with the oxytocin (OT) receptor. Similarly, cyclo-(5-9)-[Dap(5), Gly(9)]-PA, 9, had very low uterotonic potency. Two derivatives of PA truncated from the C-terminus were internally cyclized to Lys(4), giving rise to cyclo-(4-8)-desGly-NH(2)(9)[Lys(4), Arg(8)]-PA, 10 (pA(2) = 8.35 +/- 0.20), which maintains the high potency of PA and has no activity in the rat antidiuretic assay, and in the rat pressor assay it is about ten times weaker (pA2 = 6.41 +/- 0.15) than PA (pA2 = 7.47 +/- 0.35), thus showing gains in specificity, and to cyclo-(4-7)-desArg-Gly-(NH)(2)(8-9)[Lys(4), Pro(7))-PA, 11, which has much weaker potency than PA. Synthesis of cyclo-(4-6)-desPro-Arg-Gly-(NH)(2)(7-9)[Lys(4)]-PA failed.
Flouret
George
G
Department of Physiology, Northwestern University Medical School, Chicago, Illinois 60611, USA. g-flouret@northwestern.edu
Chaloin
Olivier
O
Borovickova
Lenka
L
Slaninová
Jirina
J
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010121:Oxytocin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018045:Receptors, Oxytocin / Q000819:agonists / Q000235:genetics; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects / Q000502:physiology
D006727:Hormone Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D018045:Receptors, Oxytocin; D010121:Oxytocin