Bradykinin and related kinins act on two receptor types, named B-1 and B-2. Initially identified in classical bioassays, these receptors have been cloned and characterized in binding assays performed on plasma membranes of cells expressing the native or the transfected human kinin B-1 or B-2 receptor types. The two classification criteria recommended by Schild, namely the order of potency of agonists and the actual affinity of antagonists have been found to be applicable for receptor classification based not on data only from bioassays but also from other approaches (binding assays, molecular biology techniques). The order of potency for agonists was found with naturally occurring peptides (the kinins, their desArg(9)-metabolites) and with selective agonists (e.g., [Hyp(3)]bradykinin, [Aib(7)]bradykinin): the findings obtained with agonists could be validated with various antagonists. Critical evaluation of the initial compounds, typified by D-Arg-[Hyp(3), D-Phe(7)]bradykinin, has indicated that they are short-acting, partial agonists, non-selective for the bradykinin B-2 receptor because they can be metabolized to desArg(9)-fragments that act on the kinin B-1 receptor. Use of such compounds has given rise to misunderstandings, especially with regard to new receptor types (e.g., type B-3), the existence of which was not confirmed by molecular cloning. A second generation of antagonists, represented by D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]bradykinin (HOE 140) has been found resistant to degradation, long-acting in vivo, selective and specific for the B-2 receptor and potent in all species tested. HOE 140 has been used successfully in basic pharmacology, in animal physiopathologies involving kinins and their receptors and even in clinical studies. A third generation of non-peptide B-2 receptor antagonists, whose prototype is FR 173657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-2-4-dichloro-3[(2-methyl-8-quinolinyl)oxymethyl]phenyl]-N-methylamino carbonyl-methyl]acrylamide) is now emerging and may represent substantial progress since FR 173657 is a potent orally active, selective and specific antagonist of the human and other species B-2 receptors. There is also progress regarding antagonists for the B-1 receptor. The initial compounds, especially Lys-[Leu(8)]desArg(9)-bradykinin remain among of the most potent, specific and selective B-1 antagonists which, however, show partial agonistic effects in some B-1 receptor subtypes (e.g., the mouse). Progress has been made with AcLys-[D-beta Nal(7), Ile(8)]desArg(9)-bradykinin (R 715) and Lys-Lys-[Hyp(3), Cpg(5), D-TiC7,Cpg(8)]desArg(9)-bradykinin (B 9958) which are pure B-1 antagonists in humans and rabbits; both peptides have shown resistance to degradation by peptidases and have little if any, residual agonistic activity on mouse and rat B-1 receptors. No non-peptide antagonists are yet available for the B-1 receptor. (C) 1998 Elsevier Science B.V.
