Ala scan analogues of HOE 140. Synthesis and biological activities

The role of the amino acids contained in the sequence of HOE 140 (H-DArg(1) -Arg(2)-Pro(3)-Hyp(4)-Gly(5)-Thi(6)-Ser(7)-DTic(8)-Oic(9)-Arg(10)-OH), a po tent and selective bradykinin B-2 receptor peptide antagonist, has been inv estigated by the replacement of each original residue (one by one) with Ala . The resulting set of decapeptides has been tested for the B-2 antagonist activity as well as for competition with the binding of [H-3]BK to plasma m embranes of the human umbilical vein (hUV). Positive correlations have been established between data obtained with the bioassay and with the binding i n the hUV (same species, same tissue) and also between the two bioassays, t he 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 gro ups, with Ala(1) and Ala(7) showing affinities lower than HOE 140 by a fact or of 10, Ala(4) and Ala(10) by a factor of 100 and Ala(2), Ala(5), Ala(6), Ala(8) and Ala(9) by a factor higher than 100 (100-1000). To verify the ef fect of chirality, the DAla(5) and DSer(7) analogues were synthesized and i t was found that the substitution with a D-residue in position 5 is not tol erated while that in position 7 is favourable. The DSer(7) derivative is th e most potent analogue found in this study: it shows potency as high as tha t of HOE 140 in the bioassays. (C) 2000 Editions scientifiques et medicales Elsevier SAS.