{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T22:07:55Z","timestamp":1750284475321,"version":"3.37.3"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T00:00:00Z","timestamp":1714953600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T00:00:00Z","timestamp":1714953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Psychopharmacology"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Rationale<\/jats:title>\n                <jats:p>Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Objective<\/jats:title>\n                <jats:p>Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In vitro, ITI-333 is a potent 5-HT<jats:sub>2A<\/jats:sub> receptor antagonist (K<jats:sub>i<\/jats:sub>\u2009=\u20098\u00a0nM) and a biased, partial agonist at\u00a0\u03bc-opioid (MOP) receptors (K<jats:sub>i<\/jats:sub>\u2009=\u200911\u00a0nM; lacking \u03b2-arrestin agonism) with lesser antagonist activity at adrenergic \u03b1<jats:sub>1A<\/jats:sub> (K<jats:sub>i<\/jats:sub>\u2009=\u200928\u00a0nM) and dopamine D<jats:sub>1<\/jats:sub> (K<jats:sub>i<\/jats:sub>\u2009=\u200950\u00a0nM) receptors. In vivo, ITI-333 blocks 5-HT<jats:sub>2A<\/jats:sub> receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>ITI-333 acts as a potent 5-HT<jats:sub>2A<\/jats:sub> receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal\/reinstatement, supporting its potential utility as a treatment for OUD.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00213-024-06578-w","type":"journal-article","created":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T22:01:17Z","timestamp":1715032877000},"page":"1477-1490","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders"],"prefix":"10.1007","volume":"241","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4749-686X","authenticated-orcid":false,"given":"Gretchen L.","family":"Snyder","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terry","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hailin","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David R.","family":"Maguire","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa R.","family":"Gerak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly E.","family":"Vanover","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles P.","family":"France","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,5,6]]},"reference":[{"issue":"5","key":"6578_CR1","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1177\/0269881119840521","volume":"33","author":"S Barbosa M\u00e9ndez","year":"2019","unstructured":"Barbosa M\u00e9ndez S, Salazar-Ju\u00e1rez A (2019) Mirtazapine attenuates anxiety- and depression-like behaviors in rats during cocaine withdrawal. 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(ITCI). ITI-333 is an investigational new drug under development by ITCI. GLS, PL, TM, WY, LZ, HZ, KEV, and RED are current or former employees of ITCI and may hold ITCI stock or stock options.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure\/Conflict of Interest"}}]}}