DESIGN AND SYNTHESIS OF NEW LINEAR AND CYCLIC BRADYKININ ANTAGONISTS

We report here on the synthesis and pharmacological properties of a ne w series of small linear and cyclic peptides derived from the five C-t erminal amino acid residues of second-generation bradykinin receptor a ntagonists. Variations of the two first residues of the pentapeptide ( Thi-Ser-D-Tic-Oic-Arg) were shown to modulate the biological activitie s of the analogs on bradykinin-induced smooth muscle contractions in r abbit jugular vein (RJV), a tissue preparation specific of the B2 brad ykinin receptor. Several analogs showed pA(2) values around 7 on this tissue preparation, and one cyclic compound, c[-Gly-Thi-D-Tic-Oic-Arg- ], 24, in which Thi-Ser was replaced by Gly-Thi, displayed a pA(2) of 7.4 on RJV. On the basis of these results, three cyclic molecules and their linear counterparts (compounds 22-24 and 4-6, respectively) were tested on human umbilical vein, a tissue specific of the human B2 rec eptor. The pK(B) values obtained for these compounds on these tissue p reparations were equivalent to those obtained for the decapeptide NPC 567 (4.8 < pA(2) < 5.1). NMR and molecular modeling studies performed on compound 24 clearly demonstrated a type II' beta-turn structure. Th is analog may serve as a new lead for the design of nonpeptide ligands of the bradykinin B2 receptor subtype.