NEW CYCLIC BRADYKININ ANTAGONISTS CONTAINING DISULFIDE AND LACTAM BRIDGES AT THE N-TERMINAL SEQUENCE

Continuing our studies of the bioactive conformation of bradykinin (BK ) antagonists, we synthesized a first series of analogues with side-ch ain cyclization in the N-terminal sequence. Through this conformationa l constraint it should be possible to gain insight into their three-di mensional structure. The cycles were proposed on the basis of existing ideas and hypotheses about the receptor bound conformation of BK and its antagonists. The reported peptides contain D-Phe at position 7 or D-Tic-Oic oquinoline-3-carboxyl-octahydroindole-2-carboxylic acid) at positions 7 and 8, respectively, and a disulfide or lactam bridge betw een positions 0 and 6. Syntheses, including cyclization reactions, wer e carried out on PAM resin. The biological activity of the lead compou nd [DPhe(7)]-BK, the linear precursors and the cyclic peptides, as est imated on isolated rat uterus, guinea pig ileum and lung strips, are i n the same range. The conformational properties of the new cyclic anal ogues were studied through energy minimization on a model compound. Th e results of the calculations support the existence of low-energy stru ctures containing a beta-turn. Therefore, such a turn in the N-termina l segment of the molecule can be proposed as an important structural f eature of the bioactive conformation of BK antagonists. (C) Munksgaard 1995.