Kinin B 1 Receptor Antagonists Containing α-Methyl- l -Phenylalanine: In Vitro and In Vivo Antagonistic Activities

Fernand Gobeil, Stéphanie Charland, Catherine Filteau, Stéphan I. Perron, Witold Neugebauer, Domenico Regoli
1999 Hypertension  
To protect from metabolism and to improve potency of the AcLys-[D-␤Nal 7 ,Ile 8 ]desArg 9 -bradykinin (BK) (R 715), we prepared and tested 3 analogues containing ␣-methyl-L-Phe ([ ␣ Me]Phe) in position 5: these are the AcLys-[( ␣ Me)Phe 5 ,D-␤Nal 7 ,Ile 8 ]desArg 9 BK (R 892), Lys-Lys-[( ␣ Me)Phe 5 ,D-␤Nal 7 ,Ile 8 ]desArg 9 BK (R 913), and AcLys-Lys-[( ␣ Me)Phe 5 ,D-␤Nal 7 ,Ile 8 ]desArg 9 BK (R 914). The new compounds were tested against the contractile effect induced by desArg 9 BK on 2 B 1
more » ... eceptor bioassays, the human umbilical vein, and the rabbit aorta. Their antagonistic activities were compared with those of the early prototypes (Lys-[Leu 8 ]desArg 9 BK and [Leu 8 ]desArg 9 BK) and with other recently described peptide antagonists. The 3 ( ␣ Me)Phe analogues showed high antagonistic potencies (pA 2 ) at both the human (8.8, 7.7, and 8.7, respectively) and rabbit (8.6, 7.8, and 8.6, respectively) B 1 receptors. No antagonistic effects (pA 2 Ͻ5) were observed on the B 2 receptors that mediate the contractile effects of BK on the human umbilical vein, the rabbit jugular vein, and the guinea pig ileum. Moreover, these new B 1 antagonists were found to be resistant to in vitro degradation by purified angiotensin-converting enzyme from rabbit lung. The N ␣ -acetylated forms, R 892 and R 914, were resistant to aminopeptidases from human plasma. In vivo antagonistic potencies (ID 50 ) of B 1 receptor antagonists were evaluated in anesthetized lipopolysaccharide-treated (for B 1 receptor) and nontreated (for B 2 receptor) rabbits against the hypotensive effects of exogenous desArg 9 BK and BK. R 892 efficiently inhibited (ID 50 2.8 nmol/kg IV) hypotension induced by desArg 9 BK without affecting that evoked by BK (ID 50 Ͼ600 nmol/kg IV). Conversely, the peptide antagonists Lys-Lys-[Hyp 3 ,Igl 5 ,D-Igl 7 ,Oic 8 ]desArg 9 BK (B 9858) and DArg-[Hyp 3 ,Thi 5 ,D-Tic 7 ,Oic 8 ] desArg 9 BK (S 0765) showed dual B 1 /B 2 receptor antagonism in vitro and in vivo. It is concluded that R 892 and congeners provide selective, highly potent, and metabolically stable B 1 kinin receptor antagonists that can be useful for the assessment of the physiological and pathological roles of kinin B 1 receptors. (Hypertension. 1999;33:823-829.)
doi:10.1161/01.hyp.33.3.823 pmid:10082494 fatcat:uu325aoapnczte33udaexuiivy