Kinin B-1 receptor antagonists containing alpha-methyl-L-phenylalanine: Invitro and in vivo antagonistic activities

To protect from metabolism and to improve potency of the AcLys-[D-beta Nal( 7),Ile(8)]desArg(9)-bradykinin (BK) (R 715), we prepared and tested 3 analo gues containing alpha-methyl-L-Phe ([Me-alpha]Phe) in position 5: these are the AcLys-[(Me-alpha)Phe(5),D-beta Nal(7),Ile(8)]desArg(9)BK (R 892), Lys- Lys-[(Me-alpha)Phe(5),D-beta Nal(7),Ile(8)]desArg(9)B K (R 913), and AcLys- Lys-[(alpha Me)Phe(5),D-beta Nal(7),Ile(8)]desArg(9)B K (R 914). The new c ompounds were tested against the contractile effect induced by desArg(9)BK on 2 B-1 receptor bioassays, the human umbilical vein, and the rabbit aorta . Their antagonistic activities were compared with those of the early proto types (Lys-[Leu(8)]desArg(9)BK and [Leu(8)]desArg(9)B K) and with other rec ently described peptide antagonists. The 3 (alpha Me)Phe analogues showed h igh antagonistic potencies (pA(2)) at both the human (8.8, 7.7, and 8.7, re spectively) and rabbit (8.6, 7.8, and 8.6, respectively) B-1 receptors. No antagonistic effects (pA(2)<5) were observed on the B-2 receptors that medi ate the contractile effects of BK on the human umbilical vein, the rabbit j ugular 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-alpha-acetylated forms, R 892 and R 914, were resistant to aminopeptidases from human plasma. In vivo antago nistic potencies (ID50) of B-1 receptor antagonists were evaluated in anest hetized 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 (ID50 2.8 nmol/kg IV) hypotension in duced by desArg(9)BK without affecting that evoked by BK (ID50 >600 nmol/kg IV). Conversely, the peptide antagonists Lys-Lys-[Hyp(3),Igl(5),D-Igl(7),O ic(8)]desArg(9)B K (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 usefu l for the assessment of the physiological and pathological roles of kinin B -1 receptors.