What are neurokinin 2 receptor agonists?

Recent research has identified the neurokinin 2 receptor (NK2R) as a promising target for metabolic diseases, with selective long-acting agonists reversing cardiometabolic issues in macaques [1.6.4]. So, what are neurokinin 2 receptor agonists and how do they function?

Quick Summary

Neurokinin 2 receptor agonists are compounds that bind to and activate NK2 receptors, which are predominantly found in peripheral tissues. This activation influences smooth muscle contraction, inflammation, and energy homeostasis.

Key Points

• Definition: Neurokinin 2 (NK2) receptor agonists are molecules that bind to and activate NK2 receptors, mimicking the effect of the endogenous ligand Neurokinin A (NKA) [1.5.1].

• Mechanism: As G protein-coupled receptors, NK2R activation stimulates phospholipase C, leading to increased intracellular calcium, which drives physiological responses like muscle contraction [1.8.5].

• Location: NK2 receptors are found mainly in peripheral tissues, especially the smooth muscle of the respiratory, gastrointestinal, and genitourinary tracts [1.4.1].

• Primary Effects: Activation of NK2R potently causes smooth muscle contraction (e.g., bronchoconstriction), is involved in inflammation, and can increase intestinal fluid secretion [1.4.1, 1.2.2].

• Therapeutic Shift: While research historically focused on NK2R antagonists for asthma and IBS, recent studies highlight the potential of NK2R agonists for treating obesity, metabolic disease, and bladder/bowel dysfunction [1.3.4, 1.6.4].

• Emerging Applications: Selective, long-acting NK2R agonists have been shown to reduce body weight and improve metabolic health in animal models, representing a novel approach to treating cardiometabolic diseases [1.2.4, 1.6.4].

• Research Compounds: Most NK2R agonists, such as GR-64349 and [Lys5,MeLeu9,Nle10]-NKA(4-10), are currently used as research tools to study receptor function [1.3.1, 1.9.4].

Understanding Tachykinins and Neurokinin Receptors

The neurokinin 2 (NK2) receptor is a G protein-coupled receptor (GPCR) that is part of the broader tachykinin family, which also includes the NK1 and NK3 receptors [1.4.1]. These receptors are activated by endogenous peptides called tachykinins, with each receptor showing a preferential affinity for a specific one: Substance P (SP) for NK1, Neurokinin A (NKA) for NK2, and Neurokinin B (NKB) for NK3 [1.7.5]. Neurokinin 2 receptor agonists are substances that mimic the action of NKA, binding to and activating NK2 receptors [1.5.1].

NK2 receptors are primarily expressed in peripheral tissues, including the smooth muscle of the gastrointestinal, respiratory, and urinary tracts, as well as on inflammatory cells [1.4.1, 1.6.3]. While their presence in the central nervous system (CNS) is more limited compared to NK1 and NK3 receptors, they have been identified in brain regions like the hippocampus, thalamus, and cortex, where they may play a role in mood and anxiety [1.4.2, 1.4.5].

Mechanism of Action

As G protein-coupled receptors, NK2 receptors transmit signals into the cell upon activation [1.2.5]. When a neurokinin 2 receptor agonist binds to the receptor, it triggers a conformational change that activates an associated Gq protein. This process initiates a signaling cascade that stimulates phospholipase C, leading to an increase in intracellular inositol phosphate and the mobilization of calcium [1.2.2, 1.8.5]. This surge in intracellular calcium is a key driver of many of the physiological effects associated with NK2R activation, most notably the contraction of smooth muscle cells [1.4.3].

Physiological Effects of NK2R Activation

The activation of NK2 receptors by agonists leads to a variety of physiological responses due to their widespread distribution:

• Smooth Muscle Contraction: This is one of the most significant effects. NK2R activation potently contracts smooth muscles in the airways (bronchoconstriction), gastrointestinal tract (influencing motility), and urinary bladder [1.4.1, 1.5.1, 1.5.2].
• Inflammation and Pain: NK2 receptors are implicated in neurogenic inflammation and pain pathways. Agonists can influence the release of inflammatory mediators and alter pain signaling [1.2.1, 1.5.2]. For example, stimulation of NK2 receptors on afferent neurons can lead to hyperalgesia, an increased sensitivity to pain [1.8.4].
• Cardiovascular Effects: The role in the cardiovascular system is complex. While some studies point to a role in regulating blood pressure and vascular tone, high doses of less-selective agonists can cause hypotension (low blood pressure), an effect often mediated by cross-reactivity with NK1 receptors [1.6.1, 1.8.2].
• Gastrointestinal Secretion: NK2R agonists can directly increase the secretion of water into the intestine, which can contribute to diarrhea [1.2.2].

Therapeutic Potential and Research

For many years, the primary focus of drug development around the NK2 receptor was on antagonists—drugs that block the receptor. This was due to the pro-inflammatory and bronchoconstrictive effects of NK2 activation, making antagonists logical candidates for treating conditions like asthma and irritable bowel syndrome (IBS) [1.6.5]. However, several NK2 antagonists (saredutant, ibodutant, nepadutant) failed in late-stage clinical trials due to a lack of efficacy [1.3.4].

More recently, research has pivoted to explore the therapeutic potential of NK2R agonists. This shift has been driven by several key findings:

1. Metabolic Disease and Obesity: Groundbreaking research published in Nature in 2024 revealed that activating NK2R is sufficient to suppress appetite and increase energy expenditure [1.6.4]. Scientists developed selective, long-acting NK2R agonists (like EB1002) that led to significant weight loss, improved insulin sensitivity, and reduced blood glucose, triglycerides, and cholesterol in obese mice and macaques [1.2.4, 1.3.2]. This identifies the NK2 receptor as a novel target for treating obesity and type 2 diabetes by simultaneously tackling both appetite and energy-burning pathways [1.6.4].
2. Bladder and Bowel Dysfunction: For individuals with spinal cord injury (SCI), managing bladder and bowel function is a major challenge. Research has shown that selective NK2R agonists, such as [Lys5,MeLeu9,Nle10]-NKA(4-10), can induce consistent, on-demand urination and defecation in animal models of SCI without causing tolerance over a month of dosing [1.6.2, 1.10.5]. This suggests a potential therapeutic use for these agonists to improve quality of life for patients with neurogenic bladder and bowel [1.10.1].

Comparison of Neurokinin Receptors

Feature	NK1 Receptor	NK2 Receptor	NK3 Receptor
Preferred Ligand	Substance P (SP) [1.7.5]	Neurokinin A (NKA) [1.7.5]	Neurokinin B (NKB) [1.7.5]
Primary Location	CNS and periphery (gut, immune cells) [1.7.1, 1.7.3]	Predominantly periphery (smooth muscle of airways, GI, urinary tract) [1.4.1, 1.7.1]	Primarily CNS (cortex, substantia nigra, hippocampus) [1.7.1, 1.7.3]
Key Effects of Activation	Pain transmission, neurogenic inflammation, emesis (vomiting), vasodilation [1.8.1]	Smooth muscle contraction (airways, gut, bladder), inflammation, energy expenditure [1.4.1, 1.6.4]	Modulation of dopamine pathways, reproductive hormone regulation [1.4.2, 1.7.3]
Clinical Focus	Antagonists (for anti-emetics like aprepitant and pain) [1.7.3]	Agonists (for metabolic disease, SCI-related dysfunction); Antagonists (for IBS, asthma - largely unsuccessful) [1.3.4, 1.6.4]	Antagonists (for schizophrenia, hot flashes - e.g., fezolinetant) [1.3.2, 1.7.3]

Conclusion

Neurokinin 2 receptor agonists are compounds that activate the NK2 receptor, primarily leading to smooth muscle contraction and inflammatory responses. While these effects historically led researchers to focus on blocking the receptor, recent discoveries have revealed exciting therapeutic possibilities for agonists. The development of selective, long-acting NK2R agonists has opened up new avenues for treating complex conditions like obesity, type 2 diabetes, and bladder/bowel dysfunction following spinal cord injury. As research continues to develop more selective compounds that minimize unwanted side effects (like hypotension from NK1 activation), NK2R agonists represent a promising frontier in pharmacology [1.2.4, 1.10.2].

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For further reading on the roles of tachykinin receptors, an authoritative resource is the IUPHAR/BPS Guide to PHARMACOLOGY.

https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=62

Frequently Asked Questions

What is the primary natural substance that activates the neurokinin 2 receptor?

The primary endogenous (natural) ligand that preferentially activates the neurokinin 2 (NK2) receptor is Neurokinin A (NKA) [1.7.5].

Are there any approved neurokinin 2 receptor agonist drugs on the market?

Currently, there are no approved neurokinin 2 receptor agonist drugs for clinical use. They are primarily research compounds used to investigate the receptor's function and therapeutic potential [1.3.2, 1.6.5].

What is the main difference between an NK2 agonist and an NK2 antagonist?

An NK2 agonist activates the receptor, triggering a biological response like smooth muscle contraction [1.5.1]. An NK2 antagonist blocks the receptor, preventing its activation by natural ligands like Neurokinin A, thereby inhibiting its effects [1.6.5].

What happens when NK2 receptors in the airways are activated?

Activation of NK2 receptors in the airways causes potent bronchoconstriction (narrowing of the airways) and can increase mucus production. This is why NK2 antagonists were initially explored as a treatment for asthma [1.5.2, 1.6.3].

Where are most neurokinin 2 receptors found in the body?

Neurokinin 2 receptors are predominantly found in peripheral tissues, with high concentrations in the smooth muscle of the respiratory tract (airways), gastrointestinal tract (intestines), and the genitourinary tract (urinary bladder) [1.4.1, 1.6.3].

What is the newest potential use for NK2 receptor agonists?

The newest and most promising potential use is in treating obesity and metabolic syndrome. Recent studies show that selective NK2R agonists can suppress appetite and increase energy expenditure, leading to weight loss and improved metabolic health in animal models [1.2.4, 1.6.4].

Can NK2 receptor agonists cause side effects?

Yes. Activation of NK2 receptors can cause bronchoconstriction and increased gut motility [1.5.2, 1.8.4]. Additionally, some less selective agonists can cross-react with NK1 receptors, potentially causing side effects like hypotension (low blood pressure) and dermal flushing [1.8.2, 1.10.1].