{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:54:34Z","timestamp":1791824074900,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>RAP\u2010219, a potent selective negative allosteric modulator (NAM) of \u03b1\u2010amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazolepropionic acid receptor (AMPAR) associated with \u03b38 transmembrane AMPAR regulatory protein (TARP\u03b38), is in phase 3 development for refractory focal epilepsy. This study was undertaken to assess efficacy and motor function following administration of AMPAR\/TARP\u03b38 NAMs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Single\u2010dose RAP\u2010219 (per os) efficacy was assessed in intravenous pentylenetetrazol and corneal kindling (CK) antiseizure mouse models. Single\u2010 and 7\u2010day (once daily, per os) efficacy of a RAP\u2010219 analog, RTX\u20101738, was assessed in the CK model. Pharmacokinetic and receptor occupancy (RO) studies were conducted to assess the plasma exposure and RO required for preclinical efficacy. Time to first twitch and onset of sustained clonus were recorded during intravenous pentylenetetrazol infusion following RAP\u2010219 administration. Fully kindled mice received RAP\u2010219 or RTX\u20101738 prior to corneal stimulation challenge. In parallel, plasma drug concentrations were measured in satellite groups. Motor impairment was assessed by rotarod. Hippocampal RO was determined via ex\u00a0vivo autoradiography in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the pentylenetetrazol model, .1\u2010 and 1\u2010mg\/kg RAP\u2010219 doses were associated with higher seizure threshold versus vehicle (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u2009.01). Kindled mice were fully protected from seizures by RAP\u2010219 (median effective dose [ED\n                      <jats:sub>50<\/jats:sub>\n                      ] = .02\u2009mg\/kg, median effective concentration [EC\n                      <jats:sub>50<\/jats:sub>\n                      ] =\u20092.3\u2009ng\/mL) with minimal, non\u2010dose\u2010dependent rotarod failures (therapeutic index &gt;\u2009150). RTX\u20101738 administration (single or multiple day) protected kindled mice from seizures with similar efficacy and potency (single dose: ED\n                      <jats:sub>50<\/jats:sub>\n                      = .05\u2009mg\/kg, EC\n                      <jats:sub>50<\/jats:sub>\n                      =\u20094.7\u2009ng\/mL; multiple\u2010day administration: ED\n                      <jats:sub>50<\/jats:sub>\n                      = .02\u2009mg\/kg, EC\n                      <jats:sub>50<\/jats:sub>\n                      =\u20093.6\u2009ng\/mL). RAP\u2010219 RO EC\n                      <jats:sub>50<\/jats:sub>\n                      in mice was 1.5\u2009ng\/mL, showing good correspondence of plasma exposures with the CK studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Selective inhibition of TARP\u03b38\u2010containing AMPARs provided potent, dose\u2010dependent antiseizure effects that were maintained after 7\u2010day dosing in a preclinical focal seizure model. Exposures producing antiseizure effects did not impair motor function, yielding a high therapeutic index. RAP\u2010219 may provide a new, regionally selective medicine for patients with epilepsy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70549","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:21:27Z","timestamp":1791822087000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective \u03b38 transmembrane \u03b1\u2010amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazolepropionic acid receptor regulatory protein negative allosteric modulators: Efficacy in preclinical antiseizure models"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8379-2266","authenticated-orcid":false,"given":"Jose A.","family":"Matta","sequence":"first","affiliation":[{"name":"Rapport Therapeutics, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4062-0274","authenticated-orcid":false,"given":"Brock T.","family":"Shireman","sequence":"additional","affiliation":[{"name":"Rapport Therapeutics, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9692-1275","authenticated-orcid":false,"given":"Laurie P.","family":"Volak","sequence":"additional","affiliation":[{"name":"Rapport Therapeutics, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9138-0448","authenticated-orcid":false,"given":"Michael P.","family":"Maher","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson Innovative Medicine  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5453-2956","authenticated-orcid":false,"given":"Michael K.","family":"Ameriks","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson Innovative Medicine  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4985-0164","authenticated-orcid":false,"given":"David","family":"Bredt","sequence":"additional","affiliation":[{"name":"Rapport Therapeutics, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003540\u20100"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.115.231712"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201037259\u20105"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14456"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.014135"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4221"},{"key":"e_1_2_12_8_1","volume-title":"FYCOMPA\u00ae (perampanel) tablets, for oral use, CIII; FYCOMPA\u00ae (perampanel) oral suspension, CIII [prescribing information]","year":"2023"},{"key":"e_1_2_12_9_1","volume-title":"Fycompa 2mg, 4mg, 6mg, 8mg, 10mg, 12mg film\u2010coated tablets [summary of product characteristics]","year":"2026"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2023.109283"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.121.000473"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.08.022"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.09.002"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200212116"},{"key":"e_1_2_12_15_1","unstructured":"GammaitoniA.RAP\u2010219: a novel potent and selective negative modulator of AMPAR\/TARP\u03b38. [presentation]. Presented at Epilepsy Foundation Pipeline Conference 2024 September 25\u201326 2024 Atlanta GA."},{"key":"e_1_2_12_16_1","unstructured":"Rapport Therapeutics.Pipeline. Available from:https:\/\/www.rapportrx.com\/pipeline\/#programs. Accessed Nov 2024"},{"key":"e_1_2_12_17_1","unstructured":"Rapport Therapeutics.Study evaluating the safety and efficacy of RAP\u2010219 in adult participants with refractory focal epilepsy. Clinicaltrials.gov Identifier NCT06377930. Available from:https:\/\/clinicaltrials.gov\/study\/NCT06377930"},{"key":"e_1_2_12_18_1","unstructured":"Janssen Pharmaceutica NV.3\u2010Aryl\u20102H\u2010pyrazolo[4 3\u2010b] pyridine compounds and their use as AMPA receptor modulators. 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