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.
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。