Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders

Gretchen L. Snyder, Peng Li, Terry Martin, Lei Zhang, Wei Yao, Hailin Zheng, David R. Maguire, Lisa R Gerak, Kimberly E. Vanover, Charles P. France, Robert Davis

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: 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. Objective: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. Methods: 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. Results: In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8 nM) and a biased, partial agonist at μ-opioid (MOP) receptors (Ki = 11 nM; lacking β-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT2A 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. Conclusions: ITI-333 acts as a potent 5-HT2A 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.

Original languageEnglish (US)
JournalPsychopharmacology
DOIs
StateAccepted/In press - 2024

Keywords

  • 5-HT receptor
  • Beta arrestin
  • Cue-induced heroin reinstatement
  • Morphine
  • Mu opioid receptor
  • Opioid use disorder
  • Partial agonist

ASJC Scopus subject areas

  • Pharmacology

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