A novel opioid receptor antagonist for treating abuse and overdose

摘要 阿片类药物过量导致的死亡人数继续上升;从2015年至2016年， 吸毒过量芬太尼衍生物价格低廉，易于合成，效力强，并销售给不知情的人。 滥用海洛因或其他毒品。此外，据报道芬太尼衍生物的作用更难被抑制。 与海洛因的逆转相比，纳洛酮的逆转。阿片类药物滥用的药物治疗包括： 阿片受体激动剂美沙酮和丁丙诺啡对许多患者有效， 有局限性，包括转移和滥用，它们可能产生严重的不良影响，包括 呼吸抑制和死亡。阿片受体拮抗剂纳洛酮和纳洛酮避免了滥用 责任和不良影响的美沙酮和丁丙诺啡;然而，短期的行动和 可克服性限制了它们的有效性。一种作用时间较长的药物， 逆转阿片类药物的作用的方式，而不是通过增加剂量的激动剂可以改善 通过在救援后提供难以克服的延长保护， 因为吸毒过量我们在猴子身上的初步研究表明，假不可逆的μ阿片受体选择性 拮抗剂methocinnamox（MCAM）减少海洛因，但不是可卡因自我管理，减少选择 瑞芬太尼在食物/药物选择过程中，通过以下方式逆转和保护呼吸抑制： 海洛因，一次注射有效期为一周或更长。拟议的研究建立在这些令人信服的 数据，并检查长期拮抗剂特性和MCAM与 通常滥用阿片类药物，包括强效芬太尼类似物。假设MCAM优于 纳洛酮和纳洛酮逆转和预防阿片受体激动剂的作用，特别是， 当占据相对较少的阿片受体时产生行为效应的高效激动剂。其 假不可逆结合预期使MCAM的拮抗作用更难以克服， 比目前使用的阿片受体拮抗剂具有更长的拮抗作用。目标1将描述长期 MCAM在食物/药物选择过程中对海洛因自我给药的拮抗作用。目标2将审查 MCAM拮抗芬太尼和超氧阴离子的正性增强和呼吸抑制作用的能力 单独的有效类似物以及与海洛因或可卡因的混合物。目标3将描述药代动力学特征 MCAM、海洛因、芬太尼及其衍生物和可卡因的单独和混合物。使用高度可翻译的 物种，该项目将研究一种新的阿片受体拮抗剂，有可能挽救生命， 预防和扭转阿片类药物的不良影响，往往是致命的。另一个保险箱的可用性， 有效且长效的治疗对于许多患者是有利的（例如，遵守方面的问题 将通过延长释放的假不可逆拮抗剂降低）和在许多治疗环境中（例如， 农村地区的类阿片流行病正在恶化，与治疗提供者的定期联系不切实际）。

ABSTRACT Deaths from opioid overdose continue to rise; from 2015-2016, there was a 28% increase in the number of fatal overdoses. Fentanyl derivatives are inexpensive, easy to synthesize, potent, and marketed to unsuspecting abusers as heroin or other drugs. Moreover, the effects of fentanyl derivatives are reportedly more difficult to reverse with naloxone, compared with reversal of heroin. Pharmacotherapies for opioid abuse include the µ opioid receptor agonists methadone and buprenorphine that are effective in many patients, although both drugs have limitations, including diversion and abuse, and they can have serious unwanted effects, including respiratory depression and death. The opioid receptor antagonists naltrexone and naloxone avoid the abuse liability and adverse effects of methadone and buprenorphine; however, short durations of action and surmountability limit their effectiveness. A medication with a longer duration of action that prevents and reverses the effects of opioids in a manner that is not surmounted by increasing doses of agonist could improve significantly treatment of abuse and save lives by providing insurmountable extended protection after rescue from overdose. Our pilot studies in monkeys show that the pseudoirreversible, µ opioid receptor selective antagonist methocinnamox (MCAM) decreases heroin but not cocaine self-administration, decreases choice for remifentanil in a food/drug choice procedure, and reverses as well as protects against respiratory depression by heroin, with a single injection being effective for a week or longer. Proposed studies build on these compelling data and examine the long-term antagonist properties and the pharmacokinetics of MCAM in combination with commonly abuse opioids, including ultra-potent fentanyl analogs. MCAM is hypothesized to be better than naloxone and naltrexone in reversing and preventing the effects of opioid receptor agonists and, in particular, high efficacy agonists that exert behavioral effects when occupying relatively few opioid receptors. Its pseudoirreversible binding is expected to make antagonism by MCAM more difficult to surmount and to provide longer antagonist action than the currently used opioid receptor antagonists. Aim 1 will characterize long-term antagonism of heroin self-administration by MCAM in a food/drug choice procedure. Aim 2 will examine the ability of MCAM to antagonize the positive reinforcing and respiratory depressant effects of fentanyl and ultra- potent analogs alone and in mixtures with heroin or cocaine. Aim 3 will characterize the pharmacokinetic profile of MCAM, heroin, fentanyl and its derivatives, and cocaine, alone and in mixtures. Using a highly translatable species, this project will examine a novel opioid receptor antagonist that has the potential to save lives by preventing and reversing the adverse, and often lethal, effects of opioids. The availability of another safe, effective, and long-acting treatment could be advantageous for many patients (e.g., problems with compliance would be reduced by an extended-release, pseudoirreversible antagonist) and in many treatment settings (e.g., rural areas where the opioid epidemic is worsening and regular contact with treatment providers is not practical).