ArticleBritish journal of pharmacology2019
Action of MK-7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation.
Article in British journal of pharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 89 citations in OpenAlex.
- The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial.Respiratory research · 2023Trial
- First-in-human study of eliapixant (BAY 1817080), a highly selective P2X3 receptor antagonist: Tolerability, safety and pharmacokinetics.British journal of clinical pharmacology · 2022Trial
- Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study.Clinical pharmacokinetics · 2022Trial
- Trial
- Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study.The European respiratory journal · 2021Trial
- The Genetic Architecture of Chronic Cough: From Sensory Hypersensitivity to Treatable Trait.Pulmonary therapy · 2026Review
- Induced Pluripotent Stem Cell-Based Platforms for Cardiac-Related Pain Research: Molecular Mechanisms, Experimental Models, and Therapeutic Applications.International journal of molecular sciences · 2026Review
- Vitamin B6 (Pyridoxal 5' Phosphate) antagonises carotid body P2X3 receptors in hypertension.Cardiovascular research · 2026Article
- Spinal P2XPurinergic signalling · 2026Article
- Modulation of ion channels as emerging therapeutic targets in the treatment of diabetic neuropathy.EXCLI journal · 2026Review
- Ion channels as therapeutic targets in osteoarthritis.Trends in pharmacological sciences · 2025Review
- Potent painkiller from spider venom antagonizes P2X3 receptors without dysgeusia.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Pharmacological differences between human and mouse P2X4 receptor explored using old and new tools.Purinergic signalling · 2024Article
- Molecular insights into P2X signalling cascades in acute kidney injury.Purinergic signalling · 2024Review
- Finely ordered intracellular domain harbors an allosteric site to modulate physiopathological function of P2X3 receptors.Nature communications · 2024Article
- Ion channels in osteoarthritis: emerging roles and potential targets.Nature reviews. Rheumatology · 2024Review
- Drugs Targeting Cough Receptors: New Therapeutic Options in Refractory or Unexplained Chronic Cough.Drugs · 2024Review
- Therapeutic Effects of AF219 on Interstitial Cystitis/Bladder Pain Syndrome Induced by Cyclophosphamide or Water Avoidance Stress in Rats.International urogynecology journal · 2024Article
- HSP27 Modulates Neuropathic Pain by Inhibiting P2X3 Degradation.Molecular neurobiology · 2024Article
- EU COST Action CA21130 PRESTO 'P2X receptors as therapeutic targets' inaugural meeting report.Purinergic signalling · 2023Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeThe P2X3 receptor is an ATP-gated ion channel expressed by sensory afferent neurons and is used as a target to treat chronic sensitisation conditions. The first-in-class, selective P2X3 and P2X2/3 receptor antagonist, the diaminopyrimidine MK-7264 (gefapixant), has progressed to Phase III trials for refractory or unexplained chronic cough. We used patch clamp to elucidate the pharmacology and kinetics of MK-7264 and rat models of hypersensitivity and hyperalgesia to test its efficacy on these conditions. EXPERIMENTAL APPROACH: Whole-cell patch clamp of 1321N1 cells expressing human P2X3 and P2X2/3 receptors was used to determine mode of MK-7264 action, potency, and kinetics. The analgesic efficacy was assessed using paw withdrawal threshold and limb weight distribution in rat models of inflammatory, osteoarthritic, and neuropathic sensitisation. KEY
resultsMK-7264 is a reversible allosteric antagonist at human P2X3 and P2X2/3 receptors. Experiments with the slowly desensitising P2X2/3 heteromer revealed concentration- and state-dependency to wash-on, with faster rates and greater inhibition when applied before agonist compared to during agonist application. The wash-on rate (τ value) for MK-7264 at maximal concentrations was much lower when applied before compared to during agonist application. In vivo, MK-7264 displayed efficacy comparable to naproxen in inflammatory and osteoarthritic sensitisation models and gabapentin in neuropathic sensitisation models, increasing paw withdrawal threshold and decreasing weight-bearing discomfort. CONCLUSIONS AND IMPLICATIONS: MK-7264 is a reversible and selective P2X3 and P2X2/3 antagonist, exerting allosteric antagonism via preferential activity at closed channels. Its efficacy in rat models supports its clinical investigation for chronic sensitisation conditions.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.