{"id":6289,"date":"2023-02-17T07:03:22","date_gmt":"2023-02-17T07:03:22","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2019-action-of-mk%e2%80%907264-gefapixant-at-human-p2x3-and-p2x2-3-receptors-and-in-vivo-efficacy-in-models-of-sensitisation\/"},"modified":"2023-02-17T07:03:23","modified_gmt":"2023-02-17T07:03:23","slug":"2019-action-of-mk%e2%80%907264-gefapixant-at-human-p2x3-and-p2x2-3-receptors-and-in-vivo-efficacy-in-models-of-sensitisation","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2019-action-of-mk%e2%80%907264-gefapixant-at-human-p2x3-and-p2x2-3-receptors-and-in-vivo-efficacy-in-models-of-sensitisation\/","title":{"rendered":"2019 &#8211; Action of MK\u20107264 (Gefapixant) at human P2X3 and P2X2\/3 receptors and in vivo efficacy in models of sensitisation"},"content":{"rendered":"<p>Background &#038; Purpose:The P2X3 receptor is an ATP\u2010gated ion channel expressed by sensory afferent neurons, and is as a target to treat chronic sensitisation conditions. The first\u2010in\u2010class, selective P2X3 and P2X2\/3 receptor antagonist, the diaminopyrimidine MK\u20107264 (Gefapixant), has progressed to Phase III trials for refractory or unexplained chronic cough. We have used patch\u2010clamp to elucidate the pharmacology and kinetics of MK\u20107264 and rat models of hypersensitivity and hyperalgesia to test efficacy in these conditions.Experimental Approach:Whole\u2010cell patch\u2010clamp of 1321N1 cells expressing human P2X3 and P2X2\/3 receptors was used to determine mode of MK\u20107264 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 Results:MK\u20107264 is a reversible allosteric antagonist at human P2X3 and P2X2\/3 receptors with IC<sub>50<\/sub> values of 153 and 220nM, respectively. Experiments with the slowly desensitising P2X2\/3 heteromer revealed concentration and state\u2010dependency to wash\u2010on, with faster rates and greater inhibition when applied before agonist compared to during agonist application. Wash\u2010on rate (\u03c4 value) for MK\u20107264 at maximal concentrations was 19s and 146s when applied before and during agonist application, respectively. In vivo, MK\u20107264 (30 mg\/kg) displayed efficacy comparable to naproxen (20 mg\/kg) in inflammatory and osteoarthritic sensitisation models, and gabapentin (100 mg\/kg) in neuropathic sensitisation models, increasing paw withdrawal threshold and decreasing weight bearing discomfort.Conclusions and Implications:MK\u20107264 is a reversible and selective P2X3 and P2X2\/3 antagonist, exerting allosteric antagonism via preferential activity at closed channels. Efficacy in rat models supports clinical investigation of chronic sensitisation conditions.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[45],"resource_type":[75],"application_areas":[50,76],"therapeutic_areas":[56,109],"target_categories":[337],"target_families":[358],"targets":[118,119],"resource_keyword":[],"class_list":["post-6289","resource_library","type-resource_library","status-publish","hentry","products_tags-port-a-patch","resource_type-publication","application_areas-ion-channels","application_areas-drug-discovery","therapeutic_areas-pain","therapeutic_areas-respiratory-diseases","target_categories-ligand-gated-ion-channels","target_families-p2x-receptors","targets-p2x2","targets-p2x3"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/6289","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=6289"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=6289"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=6289"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=6289"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=6289"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=6289"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=6289"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=6289"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=6289"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}