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, OM, 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 I nor 3 had activity as agonists or antagonists in the antidiuretic assay. In the pressor assay, both analogues I and 3, with pA2 = 7.05 +/- 0. 10 and pA2 = 6.77 +/- 0.12, respectively, are somewhat weaker antagonists than PA (pA2 = 7.47 +/- 0.35) showing significant gain in specificity. The [desamido(9)] PA-ethylenediamine monoamide, 6, and the dimer ([desamido9]-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-NH29[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 (pA(2) = 6.41 +/- 0.15) than PA (pA(2) = 7.47 +/- 0.35), thus showing gains in specificity, and to cyclo-(4-7)-desArg-Gly-NH28-9 (LyS(4), Pro(7))-PA, 11, which has much weaker potency than PA. Synthesis of cyclo-(4-6)-desPro-Arg-Gly-NH27-9[LyS(4)]-PA failed. Copyright (c) 2006 European Peptide Society and John Wiley & Sons, Ltd.