D. F. Elliott

Synthesis of analogues of bradykinin with replacement of the arginine residues by 4-guanidinophenyl-L-alanine

The synthesis is described of three analogues of bradykmin in which the terminal arginine residues were separately or together replaced by 4-guanidinophenyl-L-alanine. The analogues were considerably less potent than the parent peptide in their action on smooth muscle in vitro

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

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.

Synthesis of peptides containing N-2-aminoethylglycine—‘reduction analogues’

The synthesis and properties of peptides containing N-2-aminoethylglycine, the ‘reduction analogue’ of glycylglycine, are described. The ‘3,4-reduction analogue’ of [3-glycine]-bradykinin was devoid of activity in the guinea-pig ileum assay.

Synthesis of peptides related to bradykinin

The synthesis of Arg-Glyn-Arg where n= 1–7 and of Arg-Gly3-Phe-Gly3-Arg, Arg-Gly3-Phe-Gly2-Phe-Arg, and Arg-Gly6-Phe-Arg, peptide analogues of bradykinin, is described.

The solid-phase synthesis of some highly active aliphatic analogues of bradykinin

The synthesis of three analogues of bradykinin is described in which the residues of L-phenylalanine in positions 5 and 8 were separately and together replaced by β-cyclohexyl-L-alanine. The synthesis, on a solid support, utilised the salt-binding principle which led to a significant increase in coupling efficiency in comparison with previous procedures. The analogues formed were of the same order of biological potency as bradykinin itself.

Amino-acids and peptides. Part XXXII. A simplified synthesis of bradykinin by use of the picolyl ester method

The use of 4-picolyl esters for the facilitation of peptide synthesis has been further examined in a synthesis of protected bradykinin (overall yield 42%). Hydrogenation gave bradykinin with full biological activity. Prolonged hydrogenation over palladium caused partial reduction of the phenylalanine residues, and complete reduction was effected over palladium and platinum. The product, which the amino-acid analysis indicated was [5,8-β-cyclo-hexylalanine]-bradykinin, showed high bradykinin-like activity in the guinea-pig ileum test, suggesting that aromatic residues are not essential for such activity, but confirmation of this conclusion must await a full biological comparison with bradykinin itself.