Amino-acids and peptides. Part XXXIX. Synthesis of analogues of bradykinin with modifications in positions 1, 6, and 9

Abstract

The following analogues of the local tissue hormone bradykinin (I) have been synthesised by the picolyl ester ‘handle’ procedure: [1-N(ω)-methyl-L-arginine]-, [9-N(ω)-methyl-L-arginine]-, [1-N(δ)-acetimidoyl-L-ornithine]-, [9-N(δ)-acetimidoyl-L-ornithine]-, [1-N(α)-amidino-L-arginine]-, [1-N(α)-amidino-L-lysine]-, [1,9-L-ornithine]-, [6-L-ornithine]- and [6-N(δ)-(3-carboxypropionyl)-L-ornithine]-bradykinin. The first two analogues retained substantial biological activity, but the replacement of the guanidino-residues by acetamidino greatly reduced the activity, indicating a hitherto unsuspected specificity in this area. The introduction of the N(α)-amidino-groups did not greatly affect the activity. The three last-named analogues were inactive. A key step in the syntheses was the removal of the piperidino-oxycarbonyl amino-protecting group from the ornithine side-chain in the presence of t-butoxycarbonyl and nitro groups, by means of sodium dithionite.