In vitro and in vivo activity of analogues of the kinin B2 receptor antagonist MEN11270.

In this study, we describe the in vitro and in vivo activities of a series of cyclic peptide analogues of the selective kinin B[sub2] receptor antagonist MEN11270 on Chinese hamster ovary cells expressing the human B[sub2] receptor (hB[sub2] R), the human isolated umbilical vein (hUV), the isolated guinea pig ileum (gpI), and bradykinin (BK) induced bronchoconstriction (BC) and hypotension in anaesthetized guinea pigs. Substitutions in the backbone of MEN11270 (H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-DTic-Oic-Arg)c(7γ-10α)) aimed to increase the potency in inhibiting bronchospasm versus hypotension following the topical (intratracheal (i.t.)) or systemic (intravenous (i.v.)) application of these antagonists. A series of analogues were left unprotected from N-terminal cleavage by aminopeptidases (MEN12739, MEN13052, MEN13346, and MEN13371): these compounds maintained sizeable affinities for the hB[sub2] R (pK[subi] = 9.4, 9.6, 9.7, and 8.6, respectively) and antagonist activities toward BK in the hUV (pA[sub2] = 7.9, 8.3, 8.2, and 7.5) and gpI assays (pK[subB] = 7.4, 7.8, 7.9, and 7.9), but the inhibition of BK-induced BC and hypotension in vivo was negligible following either i.v. or i.t. administration. Two analogues (MEN12388 and MEN13405) could be potential substrates of angiotensin-converting enzyme: these have good activity in the hB[sub2] R (pK[subi] = 9.5 and 8.9, respectively), hUV (pA[sub2] = 8.2 for MEN12388), and gpI assays (pK[subB] = 8.4 and 8.0) but an in vivo activity 10- to 30-fold lower than the parent compound MEN11270 (pK[subi] = 9.4, pA[sub2] =8.1,pK[subB] = 8.3) when given by either the i.v. or the i.t. route. Other analogues were functionalized with a quaternary ammonium Lys... [ABSTRACT FROM AUTHOR]