Abstract

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 (K_b = 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-γ-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 NK₁ 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.