Elsevier

Autonomic Neuroscience

Volume 235, November 2021, 102865
Autonomic Neuroscience

Review
Tachykinin NK2 antagonist for treatments of various disease states

https://doi.org/10.1016/j.autneu.2021.102865Get rights and content

Abstract

Tachykinin NK2 receptors are distributed in periphery, in the smooth muscle of the respiratory, gastrointestinal, genitourinary tract, and within the brain. Substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) are endogenous ligands for NK2 receptors and are active in the peripheral and central nervous systems. NK2 antagonists have the potential to reduce airway motor responses and prevent hyperactivity by inhibiting NKA-induced bronchoconstriction in asthmatic patients. Due to its abundance, peripherally and centrally, tachykinin NK2 receptor antagonists have high potential in treating various disease states ranging from asthma to irritable bowel syndrome, to detrusor hyperactivity, to anxiety. This review is an evaluation of NK2 receptor antagonists as possible therapeutics for a myriad of pharmacological treatments.

Introduction

Tachykinins are neuropeptides with a common C-terminal, Phe-X-Gly-Leu-Met-NH2 end. There are three subtypes of tachykinin receptors, NK1, NK2, and NK3, all of which are G protein coupled. Substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) are endogenous ligands for these tachykinin receptors and are active in the peripheral and central nervous systems (Maggi et al., 1993). In the periphery, NK2 receptors are mainly located in the smooth muscle of the respiratory, gastrointestinal, and genitourinary tract (Altamura, 2011). Additionally, NK2 receptors are detected in the brain but are predominantly found in the peripheral nervous system.

Endogenous release of SP and NKA from C-fibers cause bronchospasms, coughing, and an exacerbation of asthma (Maggi et al., 1995). These are mediators for allergy, inflammation, mucus gland secretion, vasodilation, and airway microvascular leakage (Advenier et al., 1997). Thus, NK2 antagonists have the potential to reduce airway motor responses and prevent hyperactivity by inhibiting NKA-induced bronchoconstriction in asthmatic patients.

NK2 receptors are widely distributed on smooth muscle cells in the gastrointestinal (GI) tract. Its functions are known to regulate GI motility, secretion, visceral sensitivity, and smooth muscle contractility (Lecci et al., 2002). Some selective NK2 antagonists already went through clinical studies for the treatment of irritable bowel syndrome triggered by NKA. However, they have not been introduced to the market yet due to low efficacy. Further studies should be done to make NK2 antagonists a useful in GI related disorders.

C-fibers found in the urinary bladder release tachykinins including SP and NKA. The urinary bladder contracts in response to SP and NK2 receptors (Lecci et al., 1993; Maggi et al., 1995). Tachykinins take part in both nociceptive responses produced by bladder stimulation and to the normal micturition reflex. Several studies have been done to support that NK2 may be a new target for various types of bladder dysfunctions.

NK2 receptors are also found in the spinal cord and central nervous system. These have been reported to be involved in the perception of pain and anxiety. NK2 receptors are broadly distributed on brain regions such as the amygdala, hippocampus, cortex, dorsal raphe nucleus, and thalamus which are responsible for the emotional process (Hagan et al., 1993). Thus, it has become a promising target for modulation of anxiety and depression.

Due to its abundance in location peripherally and centrally, tachykinin NK2 receptor antagonists have a potential in treating various disease states such as asthma, irritable bowel syndrome, detrusor hyperactivity, and anxiety. Herein, is a review of tachykinin NK2 antagonist and possible treatments of various disease states.

Section snippets

Respiratory tract

The sensory neuropeptides SP and NKA are present within pulmonary sensory nerves and immune cells (Joos et al., 2000). In the lungs, SP and NKA produce bronchospasm, airway microvascular leakage, vasodilation, and mucus gland secretion which are the pathogenesis of inflammatory airway disorders (Barnes, 1987; Advenier et al., 1997). Bronchoconstriction is among the most prominent and extensively studied in regarding its relation with tachykinins. Patients with asthma are more sensitive to the

Gastrointestinal tract

Irritable bowel syndrome (IBS) is a gastrointestinal (GI) disorder characterized by chronic and relapsing abdominal pain and disrupted GI motility (Endo et al., 2015). The etiology of IBS is not fully known, however it involves interactions of genetic and psychosocial factors such as stress and psychological problems, dietary intolerance, allergy, disruption of the mucosal barrier, visceral hypersensitivity, dysregulation of the brain-gut axis, and changes in gut microbiota (Saito and Talley,

Genitourinary tract

Tachykinins, including SP, NKA, NKB are widely distributed in primary afferent nerves of the genitourinary tract. A study confirmed the absence of NK3 receptors and the presence of both NK1 and NK2 receptors in rat bladder (Hall et al., 1992). The presence of NK2 receptors in rat bladder was supported by the contraction achieved with MEN 10210 ([ßAla8]neurokinin A(4–10)) and GR 159897 (Choppin et al., 2002) (Fig. 3, Fig. 4). The predominant tachykinin receptor in the human bladder was found to

Central nervous system

Tachykinin NK2 receptors are known to be widely distributed in the periphery where they mediate actions such as smooth muscle contraction in airways, bladder, intestine, and blood vessels (Maggi et al., 1995). However, the existence of NK2 receptors in the central nervous system has been more difficult to confirm. An autoradiographic study on neonate rat brains using the NK2 antagonist radioligand, [3H]-GR 100679, located receptor binding sites in the hippocampus, thalamus, and cortex (Hagan et

Conclusion

Among different subtypes of tachykinin receptors, NK2 has shown opportunities as a target for therapies of various disease states. SP, NKA, and NKB are endogenous ligands for the tachykinin receptors and are found in the peripheral and central nervous systems. These ligands are released into the system and cause variety of disorders. Due to the effect of NKA and SP throughout the body, studies have evaluated NK2 receptor antagonists for selective blocking of these ligands. Some selective NK2

Declaration of competing interest

There are no conflict of interest.

Acknowledgements

The authors wish to thank the School of Pharmacy at the Massachusetts College of Pharmacy and Health Sciences University for financial support of this project.

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