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(Hypertension. 1996;28:833-839.)
© 1996 American Heart Association, Inc.

Articles

Structure-Activity Studies of B₁ Receptor–Related Peptides

Antagonists

Fernand Gobeil; Withold Neugebauer; Catherine Filteau; Daniela Jukic; Susanne Nsa Allogho; Leng Hong Pheng; Xuan Khai Nguyen-Le; Daniel Blouin; Domenico Regoli

the Department of Pharmacology, Medical School, Universite de Sherbrooke, and the Department of Obstetrics and Gynecology, Centre hospitalier universitaire de Sherbrooke (D.B.) (Quebec, Canada).

Correspondence to D. Regoli, Department of Pharmacology, Medical School, Universite de Sherbrooke, 3001 12th Ave N, Sherbrooke, Quebec J1H 5N4, Canada.

We tested several peptides related to des-Arg⁹-bradykinin as stimulants or inhibitors of B₁ (rabbit aorta, human umbilical vein) and B₂ (rabbit jugular vein, guinea pig ileum, human umbilical vein) receptors. We also incubated the compounds with purified angiotensin-converting enzyme from rabbit lung to test their resistance to degradation. We evaluated apparent affinities (in terms of the affinity constant pA₂) of compounds and their potential residual agonistic activities (^E). Bradykinin and des-Arg⁹-bradykinin were used as agonists for the B₂ and B₁ receptors, respectively. Degradation of peptides by the angiotensin-converting enzyme was prevented in the presence of a D-residue in position 7 of des-Arg⁹-bradykinin. Replacement of Pro⁷ with D-Tic combined with Leu, Ile, Ala, or D-Tic in position 8 led to weak B₁ receptor antagonists, some of which had strong residual agonistic activities on the B₂ receptor preparations. The use of D-ßNal in position 7, combined with Ile in position 8 and AcLys at the N-terminal (eg, AcLys[D-ßNal⁷,Ile⁸]des-Arg⁹-bradykinin) gave the most active B₁ receptor antagonist (pA₂ of 8.5 on rabbit aorta and human umbilical vein), which is also partially resistant to enzymatic degradation. Extension of the N-terminal end by Sar-Tyr-Ahx (used for labeling purposes) and even cold-labeling of Tyr with iodine were compatible with high, selective, and specific antagonism of the B₁ receptors. We compared some compounds with some already known B₁ receptor antagonists to underline the novelty of new peptidic compounds.

Key Words: kinins • B₁ receptors • adrenergic antagonists • rabbits • guinea pigs • human

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