Ibodutant

The tachykinin NK₂ receptor plays a key role in gastrointestinal motor function. Enteric neurons release neurokinin A (NKA), which activates NK₂ receptors on gastrointestinal smooth muscle, leading to contraction and increased motility. In patients with diarrhea-predominant irritable bowel syndrome, the NK₂ receptor antagonist ibodutant had a greater therapeutic effect in females than males. The present study aimed to determine whether gender influences the expression and activity of NK₂ receptors in human colonic smooth muscle. In vitro functional studies were performed to examine the contractile responses of colonic muscle strips to NKA and the selective NK₂ receptor agonist [Lys⁵,MeLeu⁹,Nle¹⁰]NKA(4-10). Contractions were also measured in the presence of ibodutant to determine its antagonistic potency. The signal transduction pathways coupled to NK₂ receptor activation were investigated using second messenger inhibitors. Western blot and fluorescent immunohistochemistry were conducted to determine the protein expression and localization of NK₂ receptors. NK₂ receptor-mediated contractility was greater in females compared with males. When against NKA, ibodutant was more potent in females. NK₂ receptor expression increased with age in females, but not in males. Phospholipase C-mediated signaling was less prominent in females compared with males, whereas Ca²⁺ sensitization via Rho kinase and protein kinase C appeared to be the dominant pathway in both genders. The distribution of NK₂ receptors in the human colon did not differ between the genders. Overall, gender differences exist in the expression and activity of NK₂ receptors in colonic smooth muscle. These gender distinctions should be considered in the therapeutic development of NK₂ receptor agents. SIGNIFICANCE STATEMENT: The tachykinin NK₂ receptor has been identified as a therapeutic target for the treatment of bowel and bladder dysfunctions. The present study has revealed gender-related variations in NK₂ receptor activity, signaling transduction pathways, antagonist potency, and changes in expression with age. These factors may underlie the gender differences in the treatment of diarrhea-predominant irritable bowel syndrome with NK₂ receptor antagonists. Our findings highlight that gender differences should be considered in the therapeutic development of NK₂ receptor agents.

Tachykinins act as neurotransmitters and neuromodulators in the central and peripheral nervous system. Preclinical studies and clinical trials showed that inhibition of the tachykinin receptors, mainly NK2 may constitute a novel attractive option in the treatment of irritable bowel syndrome (IBS). In this review, we focused on the role of tachykinins in physiology and pathophysiology of gastrointestinal (GI) tract. Moreover, we summed up recent data on tachykinin receptor antagonists in the therapy of IBS. Ibodutant is a novel drug with an interesting pharmacological profile, which exerted efficacy in women with diarrhea-predominant IBS (IBS-D) in phase II clinical trials. The promising results were not replicable and confirmed in phase III of clinical trials. Ibodutant is not ready to be introduced in the pharmaceutical market and further studies on alternative NK2 antagonist are needed to make NK2 antagonists useful tools in IBS-D treatment.