Abstract
Pharmacologic parameters for a novel non-peptide bradykinin (BK)-B2 receptor agonist, 8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoylcinnamidoacetyl]-N-methylamino] benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (FR 190997) (pEC50, ED50 values) and for the antagonist (E)-3-(6-acetamido-3-pyridyl)-[N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl] phenyl]-N-methylaminocarbonylmethyl] acrylamide (FR 173657) (pIC50, ID50 values) were measured using conventional contractile B2 receptor bioassays from rabbit, guinea pig and rat tissues and by mean of animal blood pressure models performed on anesthetized animals in the same species. In vitro assays (on the rabbit jugular vein and the guinea pig ileum) demonstrated that both the onset and duration of action of FR 190997 are prolonged compared to BK. These in vitro effects of FR 190997 strongly desensitized upon repeated tissue applications. Similar pEC50 values (7.7) were measured on the rabbit and the guinea pig tissues. In vivo, when injected intraarterially, FR 190997 produced hypotensive responses in rabbits and guinea pigs with ED50 values of 3.7±0.5 and 8.9±3.6 nmol/kg, respectively. Both the contractile and the hypotensive effects of FR 190997 were abolished by pretreating tissues (1 μM) or animals (0.1–0.5 μmol/kg) with d-Arg-[Hyp3,Thi5,d-Tic7,Oic8]BK (HOE 140) or FR 173657. FR 173657 (pIC50≈8.40), as well as other known antagonists (e.g., HOE 140, d-Arg-[Hyp3,d-Phe7,Leu8]BK), inhibited the in vitro myotropic effects of BK on the rabbit, guinea pig and rat tissues. FR 173657 also abrogated the in vivo hypotensive responses elicited by BK in the rabbit (ID50 57±9 nmol/kg), the guinea pig (ID50 215±56 nmol/kg) and the rat (ID50 187±50 nmol/kg). The in vivo duration of action of FR 173657 was significantly lower in the rabbit (≈20 min) than in the guinea pig and the rat (>90 min). It is concluded that the non-peptides FR 190997 and FR 173657 enable efficient activation and antagonism of rabbit and guinea pig B2 receptors. These non-peptide molecules represent a marked progress in medicinal chemistry and may be useful to define the role played by the kallikrein/kinin system in vivo.
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