Kinin B1 receptor antagonists with multi-enzymatic resistance properties

被引:39
作者
Neugebauer, W [1 ]
Blais, PA [1 ]
Hallé, S [1 ]
Filteau, C [1 ]
Regoli, D [1 ]
Gobeil, F [1 ]
机构
[1] Univ Sherbrooke, Fac Med, Inst Pharmacol, Sherbrooke, PQ J1H 5N4, Canada
关键词
bradykinin; antagonists; B-1; receptors; peptidases; metabolism;
D O I
10.1139/Y02-053
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The kinin B-1 receptor has been implicated in a variety of pathological states; therefore, potent, selective, and specific antagonists with prolonged duration of action in vivo are needed. Using R-715 (AcLys[D-beta-Nal(7),Ile(8)] desArg(9)BK) as a template, new peptides containing alpha-MePhe in position 5, Oic in position 2, and AcOrn instead of AcLys at the N-terminal were prepared and tested for their antagonist potency, their selectivity, and their specificity for the kinin B-1 receptor. In vitro metabolic stabilities toward aminopeptidase M (from human plasma), aminopeptidase P (from human platelets), and angiotensin-converting enzyme (purified from rabbit lung) were also investigated. The results of this study indicate that the three modifications applied separately are as well tolerated as they are when present conjointly in the template R-715. Indeed, pA(2) values of R-715 (ranging from 8.40 to 8.5) do not differ significantly from the analogues R-954 and R-955 (both ranging from 8.4 to 8.6) when measured at kinin B-1 receptors from rabbit aortas and human umbilical veins. Moreover, the chemical modifications utilized in the peptides R-954 and R-955 have provided resistance against aminopeptidases M and P, as well as the angiotensin-converting enzyme, unlike the early (e.g., Lys[Leu(8)]desArg(9)BK) and more recent (e.g., R-715, B-9858) generations of B-1 receptor antagonists. Ongoing in vivo assays will validate the assumption that the analogues R-954 and R-955 have a prolonged duration of action.
引用
收藏
页码:287 / 292
页数:6
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