Tachykinin NK2 receptor antagonists for the treatment of irritable bowel syndrome. 2004

Alessandro Lecci, and Angela Capriati, and Carlo Alberto Maggi
Clinical Research Department, Menarini Ricerche via Sette Santi 1, 50131 Florence, Italy. alecci@menarini-ricerche.it

Tachykinin NK2 receptors are expressed in the gastrointestinal tract of both laboratory animals and humans. Experimental data indicate a role for these receptors in the regulation of intestinal motor functions (both excitatory and inhibitory), secretions, inflammation and visceral sensitivity. In particular, NK2 receptor stimulation inhibits intestinal motility by activating sympathetic extrinsic pathways or NANC intramural inhibitory components, whereas a modulatory effect on cholinergic nerves or a direct effect on smooth muscle account for the NK2 receptor-mediated increase in intestinal motility. Accordingly, selective NK2 receptor antagonists can reactivate inhibited motility or decrease inflammation- or stress-associated hypermotility. Intraluminal secretion of water is increased by NK2 receptor agonists via a direct effect on epithelial cells, and this mechanism is active in models of diarrhoea since selective antagonists reverse the increase in faecal water content in these models. Hyperalgesia in response to intraluminal volume signals is possibly mediated through the stimulation of NK2 receptors located on peripheral branches of primary afferent neurones. NK2 receptor antagonists reduce the hyper-responsiveness that occurs following intestinal inflammation or application of stressful stimuli to animals. Likewise, NK2 receptor antagonists reduce intestinal tissue damage induced by chemical irritation of the intestinal wall or lumen. In healthy volunteers, the selective NK2 antagonist nepadutant reduced the motility-stimulating effects and irritable bowel syndrome-like symptoms triggered by intravenous infusion of neurokinin A, and displayed other characteristics that could support its use in patients. It is concluded that blockade of peripheral tachykinin NK2 receptors should be considered as a viable mechanism for decreasing the painful symptoms and altered bowel habits of irritable bowel syndrome patients.

UI MeSH Term Description Entries
D010456 Peptides, Cyclic Peptides whose amino acid residues are linked together forming a circular chain. Some of them are ANTI-INFECTIVE AGENTS; some are biosynthesized non-ribosomally (PEPTIDE BIOSYNTHESIS, NON-RIBOSOMAL). Circular Peptide,Cyclic Peptide,Cyclic Peptides,Cyclopeptide,Orbitide,Circular Peptides,Cyclopeptides,Orbitides,Peptide, Circular,Peptide, Cyclic,Peptides, Circular
D005769 Gastrointestinal Motility The motor activity of the GASTROINTESTINAL TRACT. Intestinal Motility,Gastrointestinal Motilities,Intestinal Motilities,Motilities, Gastrointestinal,Motilities, Intestinal,Motility, Gastrointestinal,Motility, Intestinal
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D043183 Irritable Bowel Syndrome A disorder with chronic or recurrent colonic symptoms without a clearcut etiology. This condition is characterized by chronic or recurrent ABDOMINAL PAIN, bloating, MUCUS in FECES, and an erratic disturbance of DEFECATION. Colitis, Mucous,Colon, Irritable,Colitides, Mucous,Irritable Bowel Syndromes,Irritable Colon,Mucous Colitides,Mucous Colitis,Syndrome, Irritable Bowel,Syndromes, Irritable Bowel
D018041 Receptors, Neurokinin-2 A class of cell surface receptors for tachykinins that prefers neurokinin A; (NKA, substance K, neurokinin alpha, neuromedin L), neuropeptide K; (NPK); or neuropeptide gamma over other tachykinins. Neurokinin-2 (NK-2) receptors have been cloned and are similar to other G-protein coupled receptors. NK-2 Receptors,Neurokinin A Receptors,Neurokinin-2 Receptors,Receptors, NK-2,Receptors, Substance K,SP-K Receptors,Substance K Receptors,NK-2 Receptor,NK-2 Receptor Site,Neurokinin-2 Receptor,SP-K Receptor,Substance K Receptor,NK 2 Receptor,NK 2 Receptor Site,NK 2 Receptors,Neurokinin 2 Receptor,Neurokinin 2 Receptors,Receptor Site, NK-2,Receptor, NK-2,Receptor, Neurokinin-2,Receptor, SP-K,Receptor, Substance K,Receptors, NK 2,Receptors, Neurokinin 2,Receptors, Neurokinin A,Receptors, SP-K,SP K Receptor,SP K Receptors

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