The role of the neurokinins (tachykinins) — substance P, neurokinin A, and neurokinin B — in the pathogenesis of irritable bowel syndrome has been the subject of considerable investigation and debate within the scientific community. Many companies have taken an interest in this research area over the last decade, but no tachykinin receptor antagonists have yet reached the market. Pfizer has an NK4 receptor antagonist (CP-122721) and both Menarini and Solvay have NK2 receptor antagonists in preclinical development. Sanofi-Synthelabo is developing a dual NK2/NK3antagonist for irritable bowel syndrome. The following sections discuss tachykinin receptor antagonists in clinical trials.
Mechanism Of Action
All of the tachykinins act as full agonists at the tachykinin receptors NK1, NK2, and NK3. Activation of these receptors in the gastrointestinal tract is associated with altered gastrointestinal motility, inflammation, secretion, and visceral hypersensitivity — all features of irritable bowel syndrome. Agents antagonizing the actions of tachykinins at tachykinin receptors in the gastrointestinal tract relax the gastrointestinal smooth muscle, thereby inhibiting contractions and, theoretically, controlling pain related to muscle spasms.
Menarini is developing the NK2 receptor antagonist nepadutant for the treatment of visceral hypersensitivity in irritable bowel syndrome and asthma. The compound is in Phase Ha trials for irritable bowel syndrome in Belgium and Sweden.
Results from in vitro studies show nepadutant to be a potent, competitive, and reversible antagonist at human NK2 receptors. Animal studies also suggest that nepadutant can reduce rectal hyperalgesia but has little effect on normal sensation. These results indicate that tachykinin NK2 receptor antagonists might not produce visceral analgesia in all patients, like opiates do, but rather they can correct visceral hyperalgesia in patients with abnormal gastrointestinal sensitivity.
Sanofi-Synthelabo is developing the tachykinin antagonist saredutant as a potential oral treatment for visceral hypersensitivity in irritable bowel syndrome; the compound is also in development for depression. In May 2003, the company announced that saredutant had entered Phase lib clinical trials for irritable bowel syndrome in France.
This agent has a mechanism of action similar to that of nepadutant — both target NK2 receptors.
Preclinical studies of the drug were presented at the 2002 Digestive Disease Week meeting. One mg/kg of saredutant given intraperitonealy reduced trimitrobenzene-sulfonate-induced rectal pain by 54%. Drug treatment did not affect colonic retention time, suggesting that saredutant could be used to treat visceral pain without causing constipation. Few data are available concerning saredutant’s tolerability; one author reported that a potential adverse event in irritable bowel syndrome patients treated with the agent may be mild frontal headache.
Talnetant is a selective NK3 antagonist under development by GSK in Europe. The agent is in Phase II clinical trials for irritable bowel syndrome, schizophrenia, and urinary incontinence.
Preclinical data for talnetant were presented at the 2002 Digestive Disease Week. Researchers carried out electrophysiological recordings of intrinsic primary afferent neuron activity in guinea pig ileum. At a concentration of 100 nM, talnetant had no effect on neuronal excitability, but it significantly reduced the amplitude of slow excitatory postsynaptic potential (EPSP) from 10.5 mV to 2.5 mV. It also reduced the ascending and descending reflexes induced by distension.