Novel Medications for Cannabis Dependence

治疗大麻依赖的新药

• 批准号: 8080344
• 负责人: Alexandros Makriyannis
• 金额: $ 56.72万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080344
• 关键词: AIDS/HIV problem; Absence of pain sensation; Address; Affinity; Agonist; Avidity; Behavioral; Behavioral Assay; Binding; Biological; Biological Assay; Biological Availability; Brain; Buprenorphine; CNR1 gene; CNR2 gene; Cannabinoids; Cannabis; Characteristics; Chemistry; Chemotherapy-Oncologic Procedure; Chronic; Clinical; Clinical Management; Cyclic AMP; Data; Dependence; Dose; Drug Addiction; Drug Design; Drug Formulations; Drug Metabolic Detoxication; Effectiveness; Evaluation; Exercise; Exhibits; Goals; In Vitro; Individual; Intention; Laboratories; Lead; Ligand Binding; Ligands; Malignant Neoplasms; Marijuana; Marijuana Dependence; Marijuana Smoking; Measures; Medication Management; Metabolic; Methadone; Mission; Modification; Monkeys; Mus; Nabilone; Nausea; Nausea and Vomiting; Opiate Addiction; Oral; Pain; Patients; Penetration; Performance; Pharmaceutical Preparations; Pharmacology; Physical Dependence; Plasma; Plasma Proteins; Preparation; Property; Protein Binding; Public Health; Rattus; Regimen; Relapse; Relative (related person); Research; Role; SR 141716A; Selection Criteria; Series; Signs and Symptoms; Stimulus; Tail; Temperature; Tetrahydrocannabinol; Time; Toxic effect; Withdrawal; Withdrawal Symptom; Work; addiction; analog; base; cannabinoid receptor; controlled release; design; drug development; drug discrimination; drug distribution; improved; in vivo; increased appetite; indexing; liquid chromatography mass spectrometry; man; natural hypothermia; nonhuman primate; novel; pre-clinical; programs; public health relevance; receptor binding; research study; response; water solubility

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.

描述（由申请人提供）：根据RFA-DA-09-001的响应，此申请旨在解决对管理大麻依赖和成瘾的新型药物的需求，这是与NIDA使命直接相关的公认公共卫生问题。 （ - ） - 非法熏制大麻的主要活性成分（Delta-9-四氢大麻醇（Delta-9-THC））在口服制剂（Dronabinol）中在法律上可用于缓解与癌症或HIV/HIV/HIV/HIV/HIV/HIV/HIV/HIV/HIV/HIV/HIV/HIV/AIV相关的疼痛和恶心。最近，它也被证明对应对可能有助于大麻成瘾和复发的戒断症状具有积极影响。但是，Delta-9-thc的口服配方均具有许多临床上不利的特性，包括差的生物利用度，不稳定的生物分配以及不可预测的对侵害和不可预测的作用。我们建议合成并有效地识别新型大麻素激动剂，这些激动剂将改善Delta-9-THC的药理特征，因此，可以作为大麻依赖性管理的可行药物。在我们的化学计划中，我们将修改Delta-9-THC和Nabilone，以产生具有改善“可吸毒性”的独特分子，即高极性，水溶性增加，并通过酶促排毒而设计用于灭活。在这种“软药物”方法中，该药物在行使其生物学作用后被酶活性灭活，以产生没有或较低活动的产品。在我们的药理学计划中，我们将使用体外措施（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，镇痛）来识别可靠的大脑能够进入大脑并具有可预测的动作时间。将在药物歧视研究中评估具有最有利的临床前特征的化合物，以评估THC样的“主观样本”效应的存在和时间过程。最后，最有希望的化合物将以反复的给药方案给出，以评估其抵消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，我们旨在开发具有改进的“可药用性”的化合物，即可预测且可控制的时间过程以及通过排毒对无活性代谢产物的灭活。我们预计，这种药物将具有抵抗大麻戒断的体征和症状的实用性，因此，物理依赖在成瘾中对大麻和其他大麻产品的作用。