Novel Medications for Cannabis Dependence

描述（由申请人提供）：本申请是根据RFA-DA-09-001设计的，解决了对新型药物的需求，以管理大麻依赖和成瘾，这是与NIDA的使命直接相关的公认的公共卫生问题。（-）-德尔塔-9-四氢大麻酚（德尔塔-9- thc）是非法吸食大麻的主要活性成分，在口服制剂（dronabinol）中可以合法获得，用于缓解与癌症或艾滋病毒/艾滋病的发生或管理相关的疼痛和恶心。最近，它也被证明对对抗可能导致大麻成瘾和复发的戒断症状有积极作用。然而，德尔塔-9-四氢大麻酚口服制剂在临床上有许多不利的特性，包括生物利用度差、不稳定的生物处置、不可预测的发病和作用抵消。我们建议合成并有效识别新的大麻素激动剂，这将改善delta-9-THC的药理学特征，因此，可能作为大麻依赖管理的可行药物。在我们的化学课程中，我们将修改δ -9- thc和纳比龙，以产生独特的分子，这些分子具有改进的“药物性”，即增加极性，水溶性，并通过酶解毒设计为失活。在这种“软药物”方法中，药物在行使其生物作用后，被酶灭活以产生没有活性或活性低得多的产品。在我们的药理学项目中，我们将使用体外测量（受体结合，功能功效，血浆和微粒体稳定性）和体内终点（脑穿透性，低温，镇痛）来确定可靠进入大脑并具有可预测的作用时间过程的新型大麻素类似物。具有最有利临床前特征的化合物将在药物鉴别研究中进行评估，以衡量thc样“主观样”效应的存在和时间过程。最后，最有希望的化合物将以重复的剂量方案给予，以评估它们对抗戒断的能力以及它们产生大麻素耐受性或依赖性的倾向。

DESCRIPTION (provided by applicant): This application, designed in response to RFA-DA-09-001, addresses the need for novel medications to manage cannabis dependence and addiction, recognized public health problems that are directly relevant to NIDA's mission. (-)-delta-9-Tetrahydrocannabinol (delta-9-THC), the principal active ingredient in illicitly smoked marijuana, is legally available in oral preparations (dronabinol) for the relief of pain and nausea associated with the occurrence or management of cancer or HIV/AIDS. Recently, it also has been shown to have positive effects in countering withdrawal symptoms that likely contribute to marijuana addiction and relapse. However, oral formulations of delta-9-THC suffer from a number of clinically unfavorable properties including poor bioavailability, erratic biodisposition, and unpredictable onsets and offsets of action. We propose to synthesize and efficiently identify novel cannabinoid agonists that will improve upon the pharmacological characteristics of delta-9-THC and that, consequently, may serve as viable medications for the management of cannabis dependence. In our chemistry program, we will modify delta-9-THC and nabilone to produce unique molecules that have improved 'druggability', i.e., increased polarity, water solubility, and designed for inactivation through enzymatic detoxification. In this 'soft drug' approach, the drug, after exercising its biological actions, is enzymatically inactivated to yield products with no or much lower activities. In our pharmacology program, we will use in vitro measures (receptor binding, functional efficacy, plasma and microsomal stability) and in vivo endpoints (brain penetrability, hypothermia, analgesia) to identify novel cannabinergic analogs that reliably enter the brain and have predictable time courses of action. Compounds with the most favorable preclinical characteristics will be evaluated in drug discrimination studies to gauge the presence and time course of THC-like 'subjective-like' effects. Finally, the most promising compounds will be given in repeated dosing regimens to evaluate their ability to counter withdrawal as well as their propensity to produce cannabinoid tolerance or dependence. PUBLIC HEALTH RELEVANCE: This project is designed to develop novel medications for the clinical management of cannabis dependence and addiction. In this work, we aim to develop compounds with improved 'druggability', i.e., predictable and controllable time course and inactivation through detoxification to inactive metabolic products. We anticipate that such drugs will have utility for countering signs and symptoms of cannabis withdrawal and, consequently, the role of physical dependence in addiction to marijuana and other cannabis products.