SELECTIVE AGONISTS OF TACHYKININ BINDING-SITES

Summary— Three types of binding sites for the mammalian tachykinins, ie Substance P (SP) Neurokinin A (NKA) and Neurokinin B (NKB), have been found in both the central and peripheral nervous systems. Substance P binds to the NK‐1 subclass of binding site while NKA and NKB are less selective endogenous ligands, which preferentially interact with the NK‐2 and NK‐3 subclasses of binding sites, respectively. Complementary strategies, including 3‐dimensional structure analysis by NMR spectroscopy and structure‐activity relationships led to the design of selective agonists of these binding sites. [Pro9] SP, [Pro10] SP and the cyclic analogues [Cys3,6, Tyr8, Pro9] SP and [Cys3,6, Tyr8, Pro10] SP are selective NK‐1 agonists. [Lys5] NKA(4–10) is a water soluble NK‐2 potent agonist. Finally, [Pro7] NKB, which completely discriminates NK‐2 and NK‐3 binding sites, is a water‐soluble NK‐3 selective agonist. 1990 Société Française de Pharmacologie et de Thérapeutique