PDF(Pubmed)
Abstract：
BACKGROUND: 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.
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.
摘要：
背景：迫切需要药物来治疗药物戒断症状，减轻导致阿片类药物滥用和复发的焦虑和精神合并症。ITI-333是一种用于治疗物质使用障碍的新型分子，精神病合并症,和痛苦。
目的：使用药理学表征ITI-333的临床前概况，行为，和生理测定。
方法：使用基于细胞的测定法来测量ITI-333的受体结合和内在功效；动物模型用于评估对阿片类药物恢复的影响，沉淀的羟考酮戒断，和药物滥用责任。
结果：体外，ITI-333是一种有效的5-HT2A受体拮抗剂（Ki=8nM），μ阿片（MOP）受体的部分激动剂（Ki=11nM；缺乏β-抑制蛋白激动作用），对肾上腺素能α1A（Ki=28nM）和多巴胺D1（Ki=50nM）受体的拮抗剂活性较小。在体内,ITI-333阻断5-HT2A受体介导的头部抽搐和MOP受体介导的对小鼠运动过度活跃的影响。单独的ITI-333是纳洛酮敏感的镇痛药（小鼠），可抑制纳洛酮沉淀的羟考酮戒断（小鼠）和海洛因提示诱导的恢复反应的躯体体征，而在长期给药后没有明显的耐受性或身体依赖性（大鼠）。ITI-333不会严重损害胃肠道或肺功能（大鼠），也不会由海洛因维持的大鼠或恒河猴静脉内自我给药。
结论：ITI-333作为一种有效的5-HT2A受体拮抗剂，以及偏向MOP受体部分激动剂，具有较低的内在功效。ITI-333减轻了阿片类药物的戒断/恢复，支持其作为OUD治疗的潜在效用。
目的：使用药理学表征ITI-333的临床前概况，行为，和生理测定。
方法：使用基于细胞的测定法来测量ITI-333的受体结合和内在功效；动物模型用于评估对阿片类药物恢复的影响，沉淀的羟考酮戒断，和药物滥用责任。
结果：体外，ITI-333是一种有效的5-HT2A受体拮抗剂（Ki=8nM），μ阿片（MOP）受体的部分激动剂（Ki=11nM；缺乏β-抑制蛋白激动作用），对肾上腺素能α1A（Ki=28nM）和多巴胺D1（Ki=50nM）受体的拮抗剂活性较小。在体内,ITI-333阻断5-HT2A受体介导的头部抽搐和MOP受体介导的对小鼠运动过度活跃的影响。单独的ITI-333是纳洛酮敏感的镇痛药（小鼠），可抑制纳洛酮沉淀的羟考酮戒断（小鼠）和海洛因提示诱导的恢复反应的躯体体征，而在长期给药后没有明显的耐受性或身体依赖性（大鼠）。ITI-333不会严重损害胃肠道或肺功能（大鼠），也不会由海洛因维持的大鼠或恒河猴静脉内自我给药。
结论：ITI-333作为一种有效的5-HT2A受体拮抗剂，以及偏向MOP受体部分激动剂，具有较低的内在功效。ITI-333减轻了阿片类药物的戒断/恢复，支持其作为OUD治疗的潜在效用。
