title: In vitro and in vivo pharmacology of S 16474, a novel dual tachykinin NK1 and NK2 receptor antagonist.
abstract: Since tachykinins released from lung sensory nerve endings are thought to play a role in inflammatory diseases of airways via NK1 and NK2 receptors, dual tachykinin NK1 and NK2 receptor antagonists may have a great therapeutic potential. In vitro, the cyclopeptide S 16474 (cyclo-[Abo-Asp(D-Trp(Suc0Na)-Phe-N-(Me)Bzl)]) bound to both human tachykinin NK1 and NK2 receptors expressed in two lines of transfected Chinese hamster ovary cells (IC50 values 85 nM and 129 nM, respectively), while showing a poor affinity for the rat tachykinin NK1 receptor. S 16474 inhibited the contractions induced by substance P in isolated rabbit vena cava (pA2 7.0) and by neurokinin A in rabbit pulmonary artery (pA2 5.6). In vivo in anaesthetized guinea-pigs, S 16474 was found to dose dependently inhibit the bronchoconstrictions induced by intravenously administered substance P, neurokinin A and capsaicin. Plasma extravasation evoked in bronchi by endogenously released tachykinins under vagus nerve stimulation was abolished by S 16474 (10 mu mol/kg i.v.). These results demonstrate clearly that S 16474 is a tachykinin receptor antagonist exhibiting, in vitro and in vivo, a dual inhibitory effect on NK1 and NK2 receptors.
authors: Division de Pneumologie, Institut de Recherches Servier, Suresnes, France.
authors: P
authors: P
authors: Robineau
authors: M
authors: M
authors: Lonchampt
authors: N
authors: N
authors: Kucharczyk
authors: J E
authors: JE
authors: Krause
authors: D
authors: D
authors: Regoli
authors: J L
authors: JL
authors: Fauchere
authors: J F
authors: JF
authors: Prost
authors: E
authors: E
authors: Canet
mesh_terms: D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C098862:S 16474; D013373:Substance P