Peripheral activity of a new NK1 receptor antagonist TAK-637 in the gastrointestinal tract.
Pathways controlling gastrointestinal function involve the activation of neurokinin NK1 receptors by substance P (SP) under normal and pathological conditions. Our aim was to pharmacologically characterize the effect of a nonpeptide NK1 receptor antagonist TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1,7]naphthyridine-6,13-dione] and determine key mechanisms of TAK-637 action in the gastrointestinal tract. Experiments were performed using intestinal preparations isolated from the guinea pig. The selective agonists of NK1 receptors, [Sar9,Met(O2)11]-SP and GR 73632 [H2N-(CH2)4-CO-Phe-Phe-Pro-NMe-Leu-Met-NH2], induced contractions in colonic longitudinal muscle pretreated with atropine. TAK-637 (1-100 nM) caused a rightward shift of the concentration-response curves showing nanomolar affinity against [Sar9,Met(O2)11]-SP (Kb = 4.7 nM) and GR 73632 (K(b) = 1.8 nM). This antagonist effect remained unchanged by tetrodotoxin. Furthermore, neither the contractions of colonic circular muscle induced by selective activation of NK2 receptors by GR 64349 (Lys-Asp-Ser-Phe-Val-Gly-R-gamma-lactam-Leu-Met-NH2) nor the responses of taenia coli induced by the selective NK3 receptor agonist senktide were affected by TAK-637 (100 nM). Studies of electrically induced neurogenic contractions showed that TAK-637 had no effect on cholinergic responses to single-pulse (0.5 ms) stimulation or stimulation with increasing frequency (1-16 Hz, 0.5 ms, 5-s train duration). In contrast, TAK-637 significantly reduced nonadrenergic, noncholinergic contractions of colonic longitudinal muscle evoked at frequencies of 8 to 16 Hz and prevented the development of capsaicin-induced contractions in isolated segments of terminal ileum. Our results indicate that TAK-637 is a selective antagonist of smooth muscle NK(1) receptors that activate intestinal muscle contraction. Additionally TAK-637 inhibits neuronal NK1 receptors involved in the "local" motor response to stimulation of capsaicin-sensitive primary afferents.
Venkova
Kalina
K
Oklahoma Foundation for Digestive Research Basic Science Laboratories, Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104, USA.
Sutkowski-Markmann
D M
DM
Greenwood-Van Meerveld
B
B
D000818:Animals; D002211:Capsaicin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004064:Digestive System / Q000187:drug effects*; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009287:Naphthyridines / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology
D009287:Naphthyridines; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; C054724:senktide; C068032:GR 73632; D013373:Substance P; C403052:TAK 637; D002211:Capsaicin