Candidate Medications for Cannabis Addiction: FAAH Inhibitors

其他项目信息--第6节--项目摘要/摘要 这项申请是根据RFA-DA-10-016设计的，解决了对新药物的需求 管理大麻依赖和成瘾，与以下直接相关的公认公共卫生问题 奈达的任务。(-)-9-四氢大麻酚(9-THC)，非法吸烟的主要有效成分 大麻，已被证明在对抗戒断症状方面有积极作用，这些症状可能有助于 大麻成瘾和复发。然而，9-THC的口服制剂在临床上存在许多问题。 不良特性，包括生物利用度差，生物处置不稳定，以及不可预测的起效和 行动的补偿。最近，我们已经证明了内源性大麻素失活酶的抑制剂 脂肪酸酰胺水解酶(FAAH)，可使内源性大麻素受体配基anandamide失活。 出乎意料的是，我们发现这些化合物中的一些与9- 它可以预测人类的重叠主观效应。与刺激效应的共性 滥用药物被认为是开发以激动剂为基础的药物的理想特征 大麻成瘾。因此，我们建议设计、合成和开发新型的FAAH抑制剂 这可能是可行的以兴奋剂为基础的药物，用于管理大麻依赖和 上瘾。在我们的化学计划中，我们将产生独特的分子来抑制FAAH，产生类似9-THC的物质 刺激作用，并具有适合临床应用的化学和药代动力学特性，即， 化学和生化稳定性以及对其他脑酯酶的选择性。在我们的 药理学计划，我们将使用体外测量(酶活性和选择性，受体结合，血浆 和微粒体稳定性)和体内终点(脑穿透性、体温过低、嗜睡和药物 鉴别)，以确定新的FAAH抑制剂为“先导”化合物。这些候选人将可靠地进入 口服给药后的大脑，有可预测的和有利的作用过程，并显示9-THC样 过敏性麻痹和低温研究中副作用低的刺激特性。与该化合物 将进一步评估最有利的临床前特征，以衡量类似THC的时间进程 “主观类”效应，产生类9-THC强化效应的倾向，衰减 9-THC的增强作用，以及9-THC处理的受试者对抗戒断的能力。

OTHER PROJECT INFORMATION - SECTION 6 - PROJECT SUMMARY/ABSTRACT This application, designed in response to RFA-DA-10-016, addresses the need for novel medications to manage cannabis dependence and addiction, recognized public health problems that are directly relevant to NIDA's mission. (-)-9-Tetrahydrocannabinol (9-THC), the principal active ingredient in illicitly smoked marijuana, has been shown to have positive effects in countering withdrawal symptoms that likely contribute to marijuana addiction and relapse. However, oral formulations of 9-THC suffer from a number of clinically unfavorable properties including poor bioavailability, erratic biodisposition, and unpredictable onsets and offsets of action. Recently, we have demonstrated that inhibitors of the endocannabinoid deactivating enzyme fatty acid amide hydrolase (FAAH) that inactivates the endogenous cannabinoid receptor ligand anandamide. Unexpectedly, we have found that some of these compounds share discriminative-stimulus properties with 9- THC, which may predict overlapping subjective effects in man. Commonality with stimulus effects of an abused drug is considered to be a desirable feature in the development of agonist-based medications for cannabis addiction. Consequently, we propose to design, synthesize, and develop novel FAAH inhibitors that may serve as viable agonist-based medications for the management of cannabis dependence and addiction. In our chemistry program, we will produce unique molecules that inhibit FAAH, produce 9-THC-like stimulus effects and have suitable chemical and pharmacokinetic characteristics for clinical application, i.e., chemical and biochemical stability as well as selectivity over other brain esterase enzymes. In our pharmacology program, we will use in vitro measures (enzyme activity and selectivity, receptor binding, plasma and microsomal stability) and in vivo endpoints (brain penetrability, hypothermia, catalepsy, and drug discrimination) to identify novel FAAH inhibitors as 'lead' compounds. These candidates will reliably enter the brain after oral administration, have predictable and favorable time courses of action, and display 9-THC-like stimulus properties with low side-effect liability in catalepsy and hypothermia studies. Compounds with the most advantageous preclinical characteristics will be further evaluated to gauge the time course of THC-like 'subjective-like' effects, the propensity to produce 9-THC -like reinforcing effects, the ability to attenuate the reinforcing effects of 9-THC, and the ability to counter withdrawal in 9-THC-treated subjects.