TT-235

Eleven new analogues were synthesized by modification of the potent oxytocin antagonist (OTA) [(S)Pmp1, D‐Trp2, Pen6, Arg8]‐Oxytocin, or PA (parent antagonist), in which (S)Pmp = β,β‐(3‐thiapentamethylene)‐β‐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)‐[Lys4, Gly9]‐PA (pA2 = 8.77 ± 0.27), 1, and cyclo‐(4–9)‐[Orn4, Gly9]‐PA (pA2 = 8.81 ± 0.25), 3, which are equipotent with PA (pA2 = 8.68 ± 0.18) in the rat uterotonic assay and cyclo‐(4–9)‐[Dab4, Gly9]‐PA, 4, cyclo‐(4–9)‐[Dap4, Gly9]‐PA, 5, and cyclo‐(4–9)‐[Pmp1, Lys4, Gly9]‐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 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 [desamido9] 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)Pmp1, Asp5]‐PA, 8, inactive in all tests, which suggests that the intact Asn5 side chain may be critical in the interaction of the OTAs with the oxytocin (OT) receptor. Similarly, cyclo‐(5–9)‐[Dap5, Gly9]‐PA, 9, had very low uterotonic potency. Two derivatives of PA truncated from the C‐terminus were internally cyclized to Lys4, giving rise to cyclo‐(4–8)‐desGly‐$\hbox{NH}_{2}^{9}$[Lys4, Arg8]‐PA, 10 (pA2 = 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‐$\hbox{NH}_{2}^{8-9}$[Lys4, Pro7)‐PA, 11, which has much weaker potency than PA. Synthesis of cyclo‐(4–6)‐desPro‐Arg‐Gly‐$\hbox{NH}_{2}^{7-9}$[Lys4]‐PA failed. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd.