Novel Medications for Cannabis Dependence

治疗大麻依赖的新药

基本信息

批准号：
8477161
负责人：
Alexandros Makriyannis
金额：
$ 53.93万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8477161
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

项目摘要

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.

描述（由申请人提供）：本申请是根据 RFA-DA-09-001 设计的，解决了对控制大麻依赖和成瘾的新型药物的需求，认识到与 NIDA 使命直接相关的公共卫生问题。 (-)-delta-9-四氢大麻酚 (delta-9-THC) 是非法吸食大麻的主要活性成分，可合法用于口服制剂（屈大麻酚），用于缓解与癌症发生或治疗相关的疼痛和恶心或艾滋病毒/艾滋病。最近，它还被证明在对抗可能导致大麻成瘾和复发的戒断症状方面具有积极作用。然而，delta-9-THC 的口服制剂具有许多临床上不利的特性，包括生物利用度差、生物处置不稳定以及作用的起效和抵消不可预测。我们建议合成并有效识别新型大麻素激动剂，这些激动剂将改善 delta-9-THC 的药理学特征，因此可以作为治疗大麻依赖的可行药物。在我们的化学项目中，我们将修改 delta-9-THC 和大麻隆，以产生独特的分子，这些分子具有改善的“成药性”，即增加极性、水溶性，并设计用于通过酶解毒失活。在这种“软药物”方法中，药物在发挥其生物作用后，通过酶促失活，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（大脑渗透性、低温、镇痛）来识别可靠进入大脑并具有可预测时间过程的新型大麻能类似物的行动。具有最有利的临床前特征的化合物将在药物辨别研究中进行评估，以衡量类似 THC 的“主观样”效应的存在和时间进程。最后，最有希望的化合物将以重复给药方案给予，以评估它们抵抗戒断的能力以及产生大麻素耐受或依赖性的倾向。