Murray Clare M, Fox J Craig, Heidbreder Christian, Young Malcolm
C4X Discovery Limited, Manchester, UK.
Indivior Inc., North Chesterfield, VA, USA.
Neurosci Appl. 2024 Mar 6;3:104053. doi: 10.1016/j.nsa.2024.104053. eCollection 2024.
There is a pressing need for novel treatments for substance use disorders to address increasing rates of addiction and drug overdose. Preclinical studies have shown that the orexin (hypocretin) system in the brain, mediated primarily by the orexin 1 receptor, plays a role in reward-related behaviours and that selective blockade of this receptor is efficacious in rodent models of addiction for a wide range of substances including opioids, cocaine, nicotine, and alcohol. We report here the preclinical profile of C4X3256, a novel, selective oral antagonist of the orexin 1 receptor. In the rat, high levels of receptor occupancy were observed in the tenia tecta region of the brain for up to 8 h following oral dosing. Translation of brain receptor occupancy into pharmacological efficacy was demonstrated in rat models showing significantly reduced nicotine self-administration and diminished cue-induced reinstatement of nicotine seeking following an oral dose of 30 mg/kg C4X3256. In addition, C4X3256 significantly reduced reinstatement of cocaine seeking induced by presentation of tone/light cues in a rat model of relapse. In summary, the nonclinical profile of C4X3256 has supported the progression of this compound into human clinical trials as an investigational medicinal product for the treatment of substance use disorders.
对于物质使用障碍，迫切需要新的治疗方法来应对不断上升的成瘾率和药物过量问题。临床前研究表明，大脑中的食欲素（下丘脑泌素）系统主要由食欲素1受体介导，在与奖赏相关的行为中起作用，并且选择性阻断该受体在包括阿片类药物、可卡因、尼古丁和酒精在内的多种物质成瘾的啮齿动物模型中有效。我们在此报告食欲素1受体新型选择性口服拮抗剂C4X3256的临床前概况。在大鼠中，口服给药后长达8小时，在大脑的带状区观察到高水平的受体占有率。在大鼠模型中证明了大脑受体占有率转化为药理效应，口服30mg/kg C4X3256后，尼古丁自我给药显著减少，线索诱导的尼古丁觅求恢复减弱。此外，在复发大鼠模型中，C4X3256显著减少了由音调/光线线索呈现诱导的可卡因觅求恢复。总之，C4X3256的非临床概况支持该化合物作为治疗物质使用障碍的研究用药品进入人体临床试验。
