Add time:09/25/2019         Source:sciencedirect.com

The role of the amino acids contained in the sequence of HOE 140 (H-DArg1-Arg2-Pro3-Hyp4-Gly5-Thi6-Ser7-DTic8-Oic9-Arg10-OH), a potent and selective bradykinin B2 receptor peptide antagonist, has been investigated by the replacement of each original residue (one by one) with Ala. The resulting set of decapeptides has been tested for the B2 antagonist activity as well as for competition with the binding of [3H]BK to plasma membranes of the human umbilical vein (hUV). Positive correlations have been established between data obtained with the bioassay and with the binding in the hUV (same species, same tissue) and also between the two bioassays, the guinea-pig ileum (GPI) and the hUV (different species, different tissue). The structure-activity study has shown that the replacement of any of the residues that constitute HOE 140 with Ala is accompanied by a decrease of potency of at least 1 log unit. The analogues can be divided into three groups, with Ala1 and Ala7 showing affinities lower than HOE 140 by a factor of 10, Ala4 and Ala10 by a factor of 100 and Ala2, Ala5, Ala6, Ala8 and Ala9 by a factor higher than 100 (100–1000). To verify the effect of chirality, the DAla5 and DSer7 analogues were synthesized and it was found that the substitution with a D-residue in position 5 is not tolerated while that in position 7 is favourable. The DSer7 derivative is the most potent analogue found in this study: it shows potency as high as that of HOE 140 in the bioassays.

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