Novel Medications for Cannabis Dependence

说明(由申请人提供)：本申请是根据RFA-DA-09-001的要求设计的，旨在解决管理大麻依赖和成瘾的新药需求，这是与NIDA的使命直接相关的公认的公共卫生问题。(-)-三角洲-9-四氢大麻酚(Delta-9-THC)是非法吸食大麻中的主要活性成分，可合法地用于口服制剂(屈诺比诺)，用于缓解与癌症或艾滋病毒/艾滋病的发生或治疗有关的疼痛和恶心。最近，它也被证明在对抗可能导致大麻成瘾和复发的戒断症状方面有积极的效果。然而，Delta-9-THC的口服制剂存在一些临床上的不利性质，包括生物利用度低、生物处置不稳定以及不可预测的起效和抵消作用。我们建议合成并有效地鉴定新的大麻素激动剂，这些激动剂将改善Delta-9-THC的药理特性，从而可能成为治疗大麻依赖的可行药物。在我们的化学计划中，我们将对Delta-9-THC和纳比隆进行修饰，以产生独特的分子，这些分子具有更好的“可药性”，即增加了极性，增加了水的溶解性，并设计为通过酶解毒来灭活。在这种“软药物”方法中，药物在发挥其生物学作用后，被酶灭活，以产生没有活性或活性低得多的产品。在我们的药理学计划中，我们将使用体外测量(受体结合、功能疗效、血浆和微粒体稳定性)和体内终点(脑渗透性、低温、止痛)来识别可靠进入大脑并具有可预测的作用过程的新型大麻能类似物。具有最有利的临床前特征的化合物将在药物鉴别研究中进行评估，以衡量类似THC的“主观类似”效应的存在和时间过程。最后，最有希望的化合物将以重复给药方案给予，以评估它们对抗戒断的能力以及产生大麻素耐受性或依赖性的倾向。 公共卫生相关性：该项目旨在开发用于大麻依赖和成瘾的临床管理的新型药物。在这项工作中，我们的目标是开发具有更好的药效性的化合物，即可预测和可控制的时间过程，并通过对非活性代谢产物的解毒来使其失活。我们预计，这些药物将有助于消除大麻戒断的迹象和症状，从而消除身体依赖对大麻和其他大麻产品成瘾的作用。

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.