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.)