Tachykinin receptor antagonists: potential in airways diseases

doi:10.1016/S1471-4892(01)00042-X

Current Opinion in Pharmacology

Volume 1, Issue 3, 1 June 2001, Pages 235-241

https://doi.org/10.1016/S1471-4892(01)00042-X Get rights and content

Abstract

Several lines of evidence indicate a role for the tachykinin peptides in airways diseases. For instance, elevated levels of tachykinins have been recovered from the airways of patients with asthma and chronic obstructive pulmonary disease (COPD), and airway inflammation leads to an upregulation of the tachykinin NK₁ and NK₂ receptors. Recent advances in tachykinin receptor pharmacology have allowed a more detailed analysis of this system and preclinical animal studies have indicated a role for the NK₁ and NK₂ receptors in bronchoconstriction, airway hyperresponsiveness and airway inflammation caused by allergic and nonallergic stimuli. In the past three years, work has entered the clinic and selective or dual-selective NK₁/NK₂ receptor antagonists appear to have the potential to affect the different aspects of asthma and COPD.

Introduction

The sensory neuropeptides substance P (SP) and neurokinin A (NKA) are members of the tachykinin family of peptides and are present within airway sensory nerves and immune cells. The tachykinins are potent broncho-constrictors, cause vasodilatation and plasma protein extravasation and exert multiple proinflammatory effects. Consequently these neuropeptides have been implicated in the pathogenesis of various aspects of asthma and chronic obstructive pulmonary disease (COPD), such as airway narrowing, airway inflammation, airway hyperresponsiveness, mucus hypersecretion and cough [1]. In experimental models the effect of sensory neuropeptides can be inhibited or prevented in various ways: by depleting the neuropeptides from the nerves (e.g. using the neurotoxin capsaicin), by inhibiting the release of sensory neuropeptides from nerves (e.g. by stimulation of presynaptic β₂-adrenoceptors or opioid receptors) or by blocking tachykinin receptors using receptor antagonists [2].

In this review the development of tachykinin receptor antagonists for use in airways diseases will be discussed, focusing particularly on articles published in the past two years. The relative importance of the three tachykinin receptors as determined in preclinical models of airways diseases together with new data on the localisation of tachykinins and their receptors in human airways are discussed. The potential for application of tachykinin receptor antagonists in asthma and COPD will be reviewed.

Section snippets

Tachykinins in normal and diseased airways

Studies on human tissue obtained at thoracotomy or autopsy, endobronchial biopsies, bronchoalveolar lavage (BAL) fluid and induced sputum indicate that the airways of patients with asthma and COPD contain elevated levels of tachykinins in comparison with normal airways [1]. In a study on induced sputum, SP concentrations were significantly higher in patients with asthma and chronic bronchitis than in healthy subjects. For all subjects, there was a correlation between the SP concentration in

Tachykinin receptors in the airways

Most of the biological actions of tachykinins are mediated by the activation of one of the three tachykinin receptors, NK₁, NK₂ and NK₃ (Table 1), which have the highest affinity for SP, NKA and neurokinin B (NKB) respectively. There is, however, a much wider crosstalk between the tachykinin peptides and their receptors than originally recognised: for instance it is presently accepted that NKA is a high affinity and effective endogenous ligand for NK₁ receptors at many synapses and/or

Preclinical airway pharmacology

In animal models, tachykinins and their receptors have been found to be involved in airway responses to nonspecific stimuli. Both NK₁ and NK₂ receptors have been implicated in airway contraction induced by cold air, hyperventilation and cigarette smoke, in plasma extravasation induced by hypertonic saline, and in airway hyperresponsiveness induced by viruses, IL-5 and NGF (Table 2); the NK₃ receptor has been implicated in citric-acid-induced cough and enhanced bronchial responsiveness (Table 2)

Conclusions

The development of tachykinin receptor antagonists for the treatment of human airways diseases has been rather slow, and so far somewhat disappointing. This is in contrast with the extensive and overwhelming preclinical data suggesting a role for tachykinins in asthma and possibly COPD. There are several explanations for this apparent paradox. Firstly, the lack of efficacy can be easily explained by the low potency or poor pharmacokinetics of some of the compounds tested so far. Potent

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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Tachykinin NK-1 and NK-2 receptor antagonists are active in various animal models of allergic asthma and chronic bronchitis. It is possible that dual NK-1/NK-2 and triple NK-1/NK-2/NK-3 tachykinin receptor antagonists have potential in the treatment of obstructive airway diseases [100,101]. CS-003 is a tachykinin receptor antagonist in development for the oral treatment of COPD.
Chronic obstructive pulmonary disease (COPD) is a major worldwide health burden with increasing morbidity, mortality and health care cost. It is a slowly progressive chronic inflammatory condition that affects the conducting airways (both large and small) and lung parenchyma. In COPD, inflammation is evident early on even in mild disease and increases with disease severity. Recent advances in our knowledge demonstrate, by comparison with asthma, the distinctive, “abnormal” or exaggerated inflammatory processes involved in the pathogenesis of COPD and thus identify novel therapeutic targets that could potentially impact on disease progression. The present review will focus on what is known of the abnormal inflammatory response of COPD in different regions of the conducting airways and lung. Novel, potentially promising approaches to therapy are presented.
Design and synthesis of 3,5-disubstituted benzamide analogues of DNK333 as dual NK<inf>1</inf>/NK<inf>2</inf> receptor probes
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N-[(R,R)-(E)-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (DNK333, 1b) has been reported to be a potent and balanced dual neurokinin (tachykinin) receptor antagonist. A recent clinical trial using DNK333 has shown that it blocks the NKA-induced bronchoconstriction in patients with asthma. A series of six analogues 3–8 derived from modification of 3,5-bis(trifluoromethyl)benzamide moiety of DNK333 has been synthesized to serve as the dual NK₁/NK₂ receptor probes. The 3,5-dinitro substituted benzamide compound 3 was found to possess potent and balanced dual NK₁/NK₂ receptor antagonist activities (pK_b = 8.4 for the NK₁ receptors, pK_b = 7.87 for the NK₂ receptors) in the functional assay using guinea pig trachea. Furthermore, SAR analysis suggests that steric, electronic, and lipophilic characteristics of substituents in the benzamide region of DNK333 have a crucial effect on both the NK₁ and NK₂ receptor antagonist activities.
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The tachykinins substance P and neurokinin A are present in human airways, in sensory nerves and immune cells. Tachykinins can be recovered from the airways after inhalation of ozone, cigarette smoke or allergen. They interact in the airways with tachykinin NK₁, NK₂ and NK₃ receptors to cause bronchoconstriction, plasma protein extravasation, and mucus secretion and to attract and activate immune cells. In preclinical studies they have been implicated in the pathophysiology of asthma and chronic obstructive pulmonary disease, including allergen- and cigarette smoke induced airway inflammation and bronchial hyperresponsiveness and mucus secretion. Dual NK₁/NK₂ or triple NK₁/NK₂/NK₃ tachykinin receptor antagonists offer therapeutic potential in airway diseases such as asthma and chronic obstructive pulmonary disease.

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ReviewTachykinin receptor antagonists: potential in airways diseases

Abstract

Introduction

Section snippets

Tachykinins in normal and diseased airways

Tachykinin receptors in the airways

Preclinical airway pharmacology

Conclusions

References and recommended reading

Trends Pharmacol Sci

J Allergy Clin Immunol

Trends Pharmacol Sci

FEBS Lett

Lancet

Eur J Pharmacol

Eur J Pharmacol

Eur J Pharmacol

Role of tachykinins in asthma

Allergy

Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide

Pharmacol Rev

Elevated Substance P content in induced sputum from patients with asthma and patients with chronic bronchitis

Am J Respir Crit Care Med

Low plasma concentrations of VIP and elevated levels of other neuropeptides during exacerbations of asthma

Eur Respir J

Neurokinin A is the predominant tachykinin in human bronchoalveolar lavage fluid in normal and asthmatic subjects

Thorax

Effects of ozone on epithelium and sensory nerves in the bronchial mucosa of healthy humans

Am J Respir Crit Care Med

Hypertonic saline nasal provocation stimulates nociceptive nerves, Substance P release, and glandular mucous exocytosis in normal humans

Am J Respir Crit Care Med

Presence of Substance P and neurokinin 1 receptors in human sputum macrophages and U-937 cells

Eur Respir J

Endogenously produced Substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation

Eur J Immunol

Induction of tachykinin gene and peptide expression in guinea pig nodose primary afferent neurons by allergic airway inflammation

J Clin Invest

Nerve growth factor: an important molecule in allergic inflammation and tissue remodelling

Int Arch Allergy Immunol

The role of neurotrophins in allergic bronchial asthma

Clin Exp Allergy

Neurotrophins are increased in bronchoalveolar lavage fluid after segmental allergen provocation

Am J Respir Crit Care Med

Hyperinnervation of the airways in transgenic mice overexpressing nerve growth factor

Am J Respir Cell Mol Biol

Nerve growth factor-induced phenotypic switch in guinea pig airway sensory neurons

Am J Respir Crit Care Med

Leukemia inhibitory factor (LIF) and LIF receptor in human lung — distribution and regulation of LIF release

Am J Respir Cell Mol Biol

Leukaemia inhibitory factor (LIF) upregulates excitatory non-adrenergic non-cholinergic and maintains cholinergic neural function in tracheal explants

Br J Pharmacol

Substance P immunoreactive nerves in airways from asthmatics and nonasthmatics

Eur Respir J

Neuropeptide-containing nerves in endobronchial biopsies from asthmatic and nonasthmatic subjects

Am J Respir Cell Mol Biol

Bronchial mucosal immunoreactivity of sensory neuropeptides in severe airway diseases

Am J Respir Crit Care Med

Increased VIP-positive nerve fibers in the mucous glands of subjects with chronic bronchitis

Am J Respir Crit Care Med

Abnormal intraepithelial airway nerves in persistent unexplained cough?

Am J Respir Crit Care Med

Role of tachykinins as contractile agonists of human airways in asthma

Clin Exp Allergy

Pharmacological analysis of the tachykinin receptors that mediate activation of nonadrenergic, noncholinergic relaxant nerves that innervate guinea pig trachealis

J Pharmacol Exp Ther

Involvement of tachykinin NK3 receptors in citric-acid-induced cough and bronchial responses in guinea pigs

Am J Respir Crit Care Med

Review
Tachykinin receptor antagonists: potential in airways diseases

Involvement of tachykinin NK₃ receptors in citric-acid-induced cough and bronchial responses in guinea pigs