{"id":3601,"date":"2026-01-05T10:13:12","date_gmt":"2026-01-05T01:13:12","guid":{"rendered":"https:\/\/misterx95.myds.me\/wordpress\/?p=3601"},"modified":"2026-01-12T10:59:26","modified_gmt":"2026-01-12T01:59:26","slug":"journal-club-26-01-05","status":"publish","type":"post","link":"https:\/\/misterx95.myds.me\/wordpress\/?p=3601","title":{"rendered":"Journal Club 26.01.05"},"content":{"rendered":"\n<p>DongYee Kim<\/p>\n\n\n\n<h2>An orally bioavailable MrgprX1-positive allosteric<br>modulator alleviates certain neuropathic pain\u2013related<br>behaviors in humanized mice<\/h2>\n\n\n\n<p>The human Mas- related G protein\u2013coupled receptor X1 (MrgprX1) represents a promising nonopioid analgesic tar<br>get because of its selective expression in primary nociceptive sensory neurons. Positive allosteric modulators (PAMs)<br>promote receptor signaling, depending on the availability of endogenous ligands, offering physiological selectivity<br>over orthosteric agonists. We developed an orally bioavailable MrgprX1 PAM, 6- tert- butyl- 5- (4- chlorophenyl)- 4- (2-<br>f<br>luoro- 6- (trifluoromethoxy)phenoxy)thieno[2,3- d]pyrimidine (BCFTP). BCFTP selectively potentiated the functional<br>response of MrgprX1 in HEK293 cells, was metabolically stable, and demonstrated a favorable in vitro safety profile.<br>BCFTP was orally bioavailable and distributed into the spinal cords of wild- type mice. BAM22, an endogenous ligand<br>for MrgprX1, was up- regulated in the spinal cord after nerve injury in both wild- type and humanized MrgprX1 mice<br>and was expressed in peptidergic and nonpeptidergic dorsal root ganglion neurons. Oral administration of BCFTP<br>dose- dependently inhibited heat hyperalgesia and spontaneous pain- like behavior but not mechanical hypersensi<br>tivity after sciatic chronic constrictive injury (CCI) in MrgprX1 mice. BCFTP did not have analgesic effects in Mrgpr<br>cluster knockout (Mrgpr\u2212\/\u2212) mice, indicating that the analgesic effects in MrgprX1 mice were MrgprX1 dependent.<br>BCFTP enhanced BAM8- 22\u2013induced, MrgprX1- mediated reduction of C- fiber eEPSC amplitudes in spinal lamina II<br>neurons, indicating inhibition of spinal nociceptive synaptic transmission. BCFTP did not induce tolerance or side<br>effects, such as itch, sedation, and motor incoordination, and had no rewarding properties. The mRNAs encoding<br>MrgprX1 and \u03bc- opioid receptors were colocalized in human DRG neurons, and BCFTP synergistically enhanced mor<br>phine analgesia in CCI MrgprX1 mice. Our research suggests an approach for developing safer, orally bioavailable<br>MrgprX1 PAM as a nonopioid therapy for neuropathic pain.<\/p>\n\n\n\n<div class=\"wp-block-file\"><object class=\"wp-block-file__embed\" data=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/01\/An-orally-bioavailable-MrgprX1-positive-allosteric.pdf\" type=\"application\/pdf\" style=\"width:100%;height:600px\" aria-label=\"Embed of An-orally-bioavailable-MrgprX1-positive-allosteric.\"><\/object><a id=\"wp-block-file--media-8b99c224-df3b-4354-afba-82c7bd295f17\" href=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/01\/An-orally-bioavailable-MrgprX1-positive-allosteric.pdf\">An-orally-bioavailable-MrgprX1-positive-allosteric<\/a><a href=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/01\/An-orally-bioavailable-MrgprX1-positive-allosteric.pdf\" class=\"wp-block-file__button wp-element-button\" download aria-describedby=\"wp-block-file--media-8b99c224-df3b-4354-afba-82c7bd295f17\">Download<\/a><\/div>\n\n\n\n<div class=\"wp-block-file\"><object class=\"wp-block-file__embed\" data=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/01\/Supplementary.pdf\" type=\"application\/pdf\" style=\"width:100%;height:600px\" aria-label=\"Embed of Supplementary.\"><\/object><a id=\"wp-block-file--media-f01e5626-d5e8-4ea2-9a09-ead387a3509a\" href=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/01\/Supplementary.pdf\">Supplementary<\/a><a href=\"https:\/\/misterx95.myds.me\/wordpress\/wp-content\/uploads\/2026\/01\/Supplementary.pdf\" class=\"wp-block-file__button wp-element-button\" download aria-describedby=\"wp-block-file--media-f01e5626-d5e8-4ea2-9a09-ead387a3509a\">Download<\/a><\/div>\n","protected":false},"excerpt":{"rendered":"<p>DongYee Kim An orally bioavailable MrgprX1-positive allostericmodulator alleviates certain neuropathic pain\u2013relatedbehaviors in humanized mice The human Mas- related G protein\u2013coupled receptor X1 (MrgprX1) represents a promising nonopioid analgesic target because of its selective expression in primary nociceptive sensory neurons. Positive allosteric modulators (PAMs)promote receptor signaling, depending on the availability of endogenous ligands, offering physiological selectivityover [&hellip;]<\/p>\n","protected":false},"author":21,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}}},"categories":[1],"tags":[],"_links":{"self":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3601"}],"collection":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/21"}],"replies":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=3601"}],"version-history":[{"count":3,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3601\/revisions"}],"predecessor-version":[{"id":3614,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3601\/revisions\/3614"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=3601"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=3601"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=3601"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}