Cyclic Analogs of Thr(6)-bradykinin, N-epsilon-Lys-bradykinin and Endo-Lys(8a)-vespulakinin-1

Syntheses are described of the endo-Lys(8a)-vespulakinin 1 and of cyclo-Thr(6)- and cyclo-N-epsilon-Lys-bradykinin. The linear peptides covering the entire sequences of endo-Lys(8a)-VSK-1 and Thr(6)-BK, and the decapeptide containing all residues constituting Lys-BK, with a Arg-Lys peptide bond involving the epsilon-amino function of lysine, were prepared by the solid-phase procedure based on Fmoc chemistry. Cyclization was carried out by the diphenylphosphorazide method. The amino-terminal octapeptide sequence of vespulakinin 1, Fmoc-Thr(tBu)-Ala-Thr(tBu)-Thr(tBu)-Arg(Pmc)-Arg(Pmc)-Arg(Pmc)-Gly-OH, and its N-alpha-Boc-[(Gal beta)Thr(3), (Gal beta)Thr(4)]-analogue, were used to prepare N-alpha-(1-8 VSK 1)-cyclo-N-epsilon-kallidin and N-alpha-[(Gal beta)Thr(3), (Gal beta)Thr(4), 1-8 VSK 1]-cyclo-N-epsilon-kallidin. Peptides and glycopeptides were characterized by amino-acid analysis, optical rotation, analytical HPLC and FAB-MS. Consistent with previous findings, preliminary pharmacological experiments on smooth muscle preparations showed that the cyclic, or partially cyclic, analogues were significatively less potent than the linear ones. (C) Munksgaard 1995.