Hoe 140 (d‐Arg‐[Hyp3, Thi5, d‐Tic7, Oic8]bradykinin) is a new bradykinin (BK)‐antagonist. It was tested in several in vitro assays and compared with d‐Arg‐[Hyp2, Thi5,8,d‐Phe7]BK. In receptor binding studies in guinea‐pig ileum preparations, Hoe 140 showed an IC50 of 1.07 × 10−9mol l−1 and a KI value of 7.98 × 10−10 mol l−1. In isolated organ preparations Hoe 140 and d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK inhibited bradykinin‐induced contractions concentration dependently, with IC50‐values in the guinea‐pig ileum preparation of 1.1 × 10−8 mol l−1 and 3 × 10−5 mol l−1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 × 10−9 mol l−1 for Hoe 140. d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK showed an IC50 of 4.0 × 10−6 mol l−1. The IC50 values in the guinea‐pig isolated pulmonary artery were 5.4 × 10−9 mol l−1 and 6.4 × 10−6 mol l−1, respectively. In the rabbit aorta no inhibitory effects on Des‐Arg9‐BK induced contractions were observed. In cultured bovine endothelial cells, Hoe 140 antagonized (IC50 = 10−8 mol l−1) bradykinin‐induced endothelium‐derived relaxing factor (EDRF) release and the bradykinin‐induced increase in cytosolic free calcium (IC50 = 10−9 mol l−1). Hoe 140 (10−7 mol l−1) totally suppressed the bradykinin‐induced (10−8 to 10−4mol l−1) prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK (10−7 mol l−1) showed a weaker antagonism. Taken together these results show that Hoe 140 is a highly potent bradykinin antagonist. It was two to three orders of magnitude more potent than d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK.

In conscious dogs, intravenous doses of 0.01 and 0.1 mgkg-1 of Hoe 140 and D-Arg-[Hyp2, Thi5'8, D-Phe7]BK were well tolerated. At doses of 1 mg kg-adverse effects occurred that were attributed to the residual BK agonistic activity of both compounds. 6 Hoe 140 has been shown to be a highly potent and long acting BK antagonist in vivo in different animal species and models. This makes it appropriate to investigate further the physiological and pathophysiological role of BK.

The astonishing discovery that peptide nucleic acids (PNAs, B=nucleobase), in spite of their drastic structural difference to natural DNA, are better nucleic acid mimetics than many other oligonucleotides has resulted in an explosion of research into this class of compounds. The synthesis, physical properties, and biological interactions of PNAs as well as their chimeras with DNA and RNA are summarized here.

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Hyp3-D-Tic7-Oic8-BK (compound II), and Arg(Tos)'-Hyp3-Thi5-D-Tic7-Oic8-BK (compound III), were tested against the effects of BK in 9 bioassay preparations including visceral smooth muscles, vasoconstriction, plasma protein extravasation, release of prostaglandin E2, bronchoconstriction, and stimulation of afferent C-fibre nociceptors. In some of these tests the effects of the new compounds were compared with those of the antagonist D-Arg0-Hyp2-Thi5'8-D-Phe7-BK (compound IV), described by