What are the antagonists for neurokinin 2 receptors?

October 12, 2025 •

3 min read

The neurokinin 2 (NK2) receptor, a member of the tachykinin receptor family, is predominantly found on smooth muscle in the periphery, including the gastrointestinal, respiratory, and urinary tracts. A range of compounds, known as neurokinin 2 receptor antagonists, have been developed to block the action of the endogenous ligand neurokinin A (NKA) at these receptors, though many have failed to reach the market despite initial promise.

Quick Summary

This article explores the primary neurokinin 2 receptor antagonists, detailing key examples like saredutant, ibodutant, and nepadutant. It explains their mechanisms for blocking neurokinin A, intended therapeutic applications, and the challenges faced in clinical trials due to limited efficacy.

Key Points

Key Antagonists: Examples of neurokinin 2 (NK2) receptor antagonists include saredutant, ibodutant, and nepadutant, which are all non-peptide compounds.
Failed Clinical Trials: Prominent NK2 antagonists like saredutant for depression and ibodutant for IBS failed in clinical trials, often due to a lack of significant efficacy over placebo.
Broad Therapeutic Potential: NK2 antagonists were investigated for a wide array of conditions, including gastrointestinal disorders (IBS), respiratory diseases (asthma), urinary issues, and psychiatric conditions (anxiety, depression).
Mechanism of Action: They work by competitively blocking the NK2 receptor, preventing its activation by the endogenous ligand neurokinin A and thereby inhibiting smooth muscle contraction and other physiological effects.
Dual Antagonism: Research has also explored dual-target antagonists, such as DNK333 and AVE5883, which block both NK1 and NK2 receptors to potentially achieve broader therapeutic effects, particularly in respiratory diseases.
Lessons Learned: Clinical trial failures have highlighted the complexities of tachykinin signaling, including interspecies variation and redundant pathways, prompting new research into more targeted or multi-target agents.

Understanding Neurokinin 2 Receptors

Neurokinin 2 receptors are a type of G-protein-coupled receptor belonging to the tachykinin family. Tachykinins are neuropeptides that modulate physiological processes in the CNS and periphery. The main ligand for the NK2 receptor is neurokinin A (NKA), which affects smooth muscle contraction in the respiratory, gastrointestinal, and genitourinary tracts.

Activating NK2 receptors with NKA can increase GI motility, cause bronchoconstriction, and contract the bladder. Due to their widespread location, NK2 receptors have been investigated for conditions involving motor and sensory dysfunction, including IBS, asthma, anxiety, and detrusor hyperactivity. Antagonists aim to block these receptors, preventing NKA's actions and potentially easing symptoms of excessive receptor activation.

Major Neurokinin 2 Receptor Antagonists

Both peptide and non-peptide NK2 receptor antagonists have been developed. Non-peptide antagonists like saredutant, ibodutant, and nepadutant have been more studied in clinical trials.

Saredutant (SR-48968)

Saredutant was a non-peptide NK2 antagonist developed for major depressive disorder and generalized anxiety disorder. Preclinical studies showed potential anxiolytic and antidepressant effects. However, development was stopped after Phase III trials did not show significant improvement over placebo.

Ibodutant

Ibodutant is another selective NK2 antagonist studied for IBS-D. A Phase II trial indicated it was more effective in females. However, further development was discontinued due to low overall efficacy.

Nepadutant (MEN-11420)

Nepadutant is a potent and selective NK2 antagonist investigated for GI motility regulation. Studies showed it blocked NKA-stimulated motility in humans but did not affect normal motility. Its therapeutic development also faced efficacy issues.

Mechanisms of Action

These antagonists work by competitive inhibition, binding to the NK2 receptor and preventing NKA from activating it. This blockade can help manage conditions like IBS-D or asthma characterized by excessive smooth muscle contraction. Structural studies have provided insights into how agonists and antagonists interact with the receptor.

Clinical Challenges and Research Shifts

Clinical trials for NK2 antagonists have often been unsuccessful. Reasons include:

Low Clinical Efficacy: Many trials failed to show significant symptom improvement over placebo.
Interspecies Variation: Differences in NK2 receptor pharmacology between animals and humans may lead to inaccurate preclinical results.
Redundancy: Other tachykinin receptors or signaling pathways might compensate for NK2 blockade.

These challenges have led to research into dual or triple tachykinin antagonists, like DNK333 (NK1/NK2) and AVE5883 (NK1/NK2), hoping for broader effects. Some research is also exploring NK2 agonists for metabolic conditions.

Comparison of Key NK2 Receptor Antagonists


Antagonist Name	Primary Target	Investigated Conditions	Clinical Trial Status	Key Outcome / Note
Saredutant (SR-48968)	Selective NK2	Major depressive disorder, generalized anxiety disorder	Phase III trials failed due to lack of significant efficacy over placebo.	Also had preclinical anxiolytic effects.
Ibodutant	Selective NK2	IBS with diarrhea (IBS-D)	Phase II trial completed; showed greater effect in females, but overall development discontinued.	Confirmed gender-related differences in NK2 receptor activity.
Nepadutant (MEN-11420)	Selective NK2	GI motility disorders, infant colitis	Investigated in clinical studies but failed to reach market due to low efficacy.	Blocked stimulated, but not basal, GI motility.
DNK333	Dual NK1/NK2	IBS-D	Phase II studies showed promise in women.	Example of exploring broader tachykinin blockade.
AVE5883	Dual NK1/NK2	Asthma	Failed to reduce allergen-induced airway responses in asthmatics.	Highlights challenges of complex inflammatory pathways.

Future Perspectives

Research into NK2 receptors continues, exploring roles in conditions like neuropathic pain and neuroinflammation. Lessons from past failures are guiding the development of more sophisticated compounds, including multi-target agents. Better understanding of species differences and interactions with other systems is crucial.

Future work may explore interactions with systems like the GABA system or developing compounds with tissue-specific effects. While challenging, past experiences are shaping the development of more targeted therapies.

Conclusion

The development of NK2 receptor antagonists like saredutant, ibodutant, and nepadutant highlighted the potential of blocking neurokinin A. Although clinical trials for conditions like depression and IBS were disappointing, they provided valuable insights into disease complexity and receptor pharmacology. These studies demonstrated the limitations of targeting a single tachykinin receptor and emphasized the need for more targeted or multi-target strategies. Future research will build on this knowledge to develop more effective therapies for NK2-related pathways.

For more information on the history and classification of tachykinin receptors, including NK2, a helpful resource is the IUPHAR/BPS Guide to Pharmacology at https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=62.

Frequently Asked Questions

The neurokinin 2 (NK2) receptor is involved in regulating smooth muscle contraction in several parts of the body, including the gastrointestinal, respiratory, and urinary tracts. Its activation is mediated by the neuropeptide neurokinin A (NKA).

NK2 receptor antagonists failed in many clinical trials primarily due to limited efficacy, meaning they did not show a significantly better therapeutic effect than a placebo. Reasons for this may include species-specific differences in receptor function and the complexity of the diseases they were intended to treat.

No, despite significant research and clinical trials, no selective neurokinin 2 receptor antagonist has been introduced to the market for therapeutic use. Some dual antagonists targeting NK1/NK2 have been investigated, but also faced challenges.

Saredutant (SR-48968) is a non-peptide NK2 receptor antagonist that was developed for major depressive disorder and generalized anxiety disorder. Its development was terminated after it failed to demonstrate significant efficacy in Phase III clinical trials.

Ibodutant is a selective NK2 antagonist investigated for irritable bowel syndrome with diarrhea (IBS-D). A Phase II study showed a more significant improvement in symptoms for female patients, but overall development was discontinued.

NK2 receptor antagonists have been explored for a wide range of conditions, including irritable bowel syndrome (IBS), asthma, anxiety, major depressive disorder, and overactive bladder (detrusor hyperactivity).

A selective NK2 antagonist, such as saredutant, targets only the NK2 receptor. A dual antagonist, like DNK333, is designed to block more than one type of tachykinin receptor, such as both NK1 and NK2, with the goal of broader therapeutic effects.

Yes, research is ongoing, but the focus has evolved. Some projects are investigating multi-target ligands (e.g., opioid-NK2 antagonists) for pain management, while other studies have surprisingly explored NK2 agonists for metabolic conditions.