{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T17:22:13Z","timestamp":1783012933179,"version":"3.54.6"},"reference-count":41,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["RO1MH122205"],"award-info":[{"award-number":["RO1MH122205"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>\n                      The muscarinic agonist xanomeline, in combination with the peripherally restricted muscarinic antagonist trospium, has recently been approved for treatment of schizophrenia. Xanomeline represents the first approved antipsychotic drug without apparent activity at D\n                      <jats:sub>2<\/jats:sub>\n                      \u2010dopamine receptors. In humans, xanomeline is reported to be metabolised to N\u2010desmethylxanomeline, which has a similar pharmacokinetic profile to xanomeline, although its pharmacology has not been reported.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>We profiled xanomeline and N\u2010desmethylxanomeline using radioligand binding assays, PRESTO\u2010Tango screening across the human GPCRome, and orthogonal functional assays (TRUPATH BRET2 G\u2010protein dissociation, BRET1 \u03b2\u2010arrestin recruitment, calcium flux and GloSensor cAMP). We summarised signalling with transduction coefficients and clustered these values.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>We discovered that xanomeline and N\u2010desmethylxanomeline have potent agonist and antagonist actions at many biogenic amine G\u2010protein coupled receptors. These results suggest that at least some of the actions of xanomeline and N\u2010desmethylxanomeline could be mediated by off\u2010target actions at serotonergic, dopaminergic, histaminergic, adrenergic and other receptors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>These standardised receptorome\u2010wide data identify candidate secondary targets beyond muscarinic receptors that may contribute to efficacy and\/or tolerability, depending on exposure and target engagement. The dataset provides a quantitative framework for prioritising targets for mechanistic follow\u2010up and optimising muscarinic\u2010based therapeutics. We discuss the potential implications of these findings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70460","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T01:14:36Z","timestamp":1776993276000},"page":"4215-4226","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The polypharmacological profiles of xanomeline and N\u2010desmethylxanomeline"],"prefix":"10.1111","volume":"183","author":[{"given":"Kensuke","family":"Sakamoto","sequence":"first","affiliation":[{"name":"NIMH Psychoactive Drug Screening Program and the Department of Pharmacology UNC Chapel Hill Medical School  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi\u2010Ping","family":"Huang","sequence":"additional","affiliation":[{"name":"NIMH Psychoactive Drug Screening Program and the Department of Pharmacology UNC Chapel Hill Medical School  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia L.","family":"Albert","sequence":"additional","affiliation":[{"name":"NIMH Psychoactive Drug Screening Program and the Department of Pharmacology UNC Chapel Hill Medical School  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma M.","family":"Knobloch","sequence":"additional","affiliation":[{"name":"NIMH Psychoactive Drug Screening Program and the Department of Pharmacology UNC Chapel Hill Medical School  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace K.","family":"Foland","sequence":"additional","affiliation":[{"name":"NIMH Psychoactive Drug Screening Program and the Department of Pharmacology UNC Chapel Hill Medical School  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan L.","family":"Roth","sequence":"additional","affiliation":[{"name":"NIMH Psychoactive Drug Screening Program and the Department of Pharmacology UNC Chapel Hill Medical School  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16176"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.21823"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11691"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1983.0093"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1997.00550160091022"},{"issue":"4","key":"e_1_2_11_7_1","first-page":"S16","article-title":"The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease","volume":"11","author":"Bodick N. 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