Cyclic analogues of bradykinin containing a carboxyl group
I. Mutule, F. Mutulis, N. Myshliakova, M. Veveris, V. Golubeva, E. Porunkevich, M. Ratkevich, G. Strazda, V. Klusa, J. Bergmann, I. Sekacis, V. Grigoryeva, A. Sulima, G. Chipens
Institute of Organic Synthesis, Latvian Academy of Sciences, Riga; Zentralinstitut fiir Molecularbiologie, AdW der DDR, Berlin; M. M. Shemyakin Institute of Bioorganic Chemistry, Academy of Sciences of the USSR, Moscow
Abstract: 1α-β-carboxypropionyl-cyclo(9→1ε-[Lys1, Gly6]bradykinin (Suc-cILys1, Gly6]B), 1α-β-carboxypropionyl-cyclo(10→1ε)kallidin (Suc-cK), cyclo(10γ→1ε)-[Glu10]kallidin (c[Glu10]K) and cyclo(11γ→1ε)kallidylglutamic acid (cKG) were synthesized. Suc-c[Lys1, Gly6]B and Suc-cK were prepared by acylating the appropriate cyclopepti-des with succinic anhydride. c[Glu10]K and cKG were obtained by the classic peptide synthesis, the cyclization being carried out with 61 and 42% yields, respectively. The protecting groups were then eliminated by catalytic hydrogenation. c[Glu10]K and cKG exerted myotropic action on isolated rat uterus (α 0.73 and 0.89, pD2 6.61 and 8.61, respectively). cKG displayed direct myotropic activity with respect to electrically stimulated rat vas deferens and guinea-pig ileum, potentiating the contractions (by 100%) in response to electric stimuli. c[Glu10]K and cKG elicit histamine release in isolated rat mast cells (EC30 4.91-10-5 and 1.47-10-6 M, respectively). Both cyclopeptides alter arterial pressure following intravenous administration to anaesthetized rats, cats and dogs and affect heart rate. In all assays cKG is more active than c[Glu10]K. Suc-c[Lys1, Gly6]B and Suc-cK do not possess myotropic, histamine-releasing or hypotensive activity, though they were found to elicit a transient increase of bloodflow in cats and dogs.
Russian Journal of Bioorganic Chemistry 1990, 16 (11):1465-1476