tak-637 and senktide

This study investigates the effect of a selective NK(1) receptor antagonist TAK-637 on enteric mechanisms involved in regulation of epithelial secretion in the colon. Mucosal sheets isolated from guinea-pig colon were placed in modified Ussing chambers and the net active transport of electrolytes was measured as short-circuit current (Isc). GR-73632, a selective NK(1) receptor agonist, induced an increase in basal Isc, which was inhibited by TAK-637 (IC(50) of 21 nM). The increase in Isc induced by GR-73632 was significantly attenuated by tetrodotoxin (TTX, 1 microM), indicating that TAK-637 inhibits neuronal NK(1) receptors. Moreover, TAK-637 reduced the TTX-resistant component of the response to GR-73632 suggesting that NK(1) receptors expressed by epithelial cells are inhibited by TAK-637. In separate experiments, TAK-637 partially inhibited the submaximal Isc induced by electrical field stimulation (EFS, 0.5 ms, 15 Hz) of enteric nerves or by activation of primary afferent fibers using capsaicin (50 microM). TAK-637 had no significant effect on the basal Isc or on responses induced by neurokinin A (NKA), senktide, or forskolin. The results imply that inhibition of peripheral NK(1) receptors may reduce autonomic epithelial secretion in response to activation of autonomic secretomotor pathways, while having no significant effect on basal epithelial transport.

Topics: Animals; Capsaicin; Colforsin; Colon; Electric Stimulation; Electrophysiology; Guinea Pigs; In Vitro Techniques; Intestinal Absorption; Intestinal Mucosa; Male; Naphthyridines; Neurokinin A; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Receptors, Neurokinin-1; Statistics, Nonparametric; Substance P; Tetrodotoxin

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.

Topics: Animals; Capsaicin; Digestive System; Electric Stimulation; Guinea Pigs; In Vitro Techniques; Isometric Contraction; Male; Muscle, Smooth; Naphthyridines; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Substance P