Medications for Synthetic Cannabinoid Abuse

合成大麻素滥用药物

• 批准号: 9558524
• 负责人: Alexandros Makriyannis
• 金额: $ 22.5万
• 依托单位: PAFOSPHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9558524
• 关键词: Accident and Emergency department; Admission activity; Affinity; Agonist; Anhedonia; Animals; Antidotes; Attenuated; Back; Behavior; Behavioral Paradigm; Biological Assay; Brain; CNR1 gene; CNR2 gene; Cannabis; Cardiac Death; Cardiotoxicity; Cell membrane; Characteristics; Clinical; Clinical Services; Complex; Consumption; Convulsions; Crystallization; Cyclic AMP; Data; Designer Drugs; Development; Devices; Docking; Dose; Emergency response; FDA approved; Formulation; Free Energy; Future; Gender; Generations; Goals; Grant; Hand; Human; In Vitro; Industry; Lead; Letters; Life; Ligands; Liver Microsomes; Marijuana; Measures; Metabolic; Mus; Naloxone; Naltrexone; Narcan; Nausea; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Plasma; Poison; Poison Control Centers; Preparation; Procedures; Property; Psychotic Disorders; Reaction; Reaction Time; Recording of previous events; Reporting; Reproducibility; Rodent; Rodent Model; Safety; Seizures; Services; Small Business Technology Transfer Research; Smoke; Structure; System; Testing; Tetrahydrocannabinol; Toxic effect; Toxicokinetics; Tremor; Universities; Visit; Whole Blood; Withdrawal; analog; base; design; drug discovery; esterase; improved; in vivo; lead optimization; liquid chromatography mass spectrometry; meetings; method development; natural hypothermia; neurotoxic; neurotoxicity; novel; opioid overdose; phase 2 study; pre-clinical; preclinical evaluation; preclinical study; prototype; receptor binding; response; rimonabant; side effect; synthetic cannabinoid; translational model; water solubility

PROJECT SUMMARY/ABSTRACT In response to PA-17-303, this Phase I STTR proposal will aim at developing pharmacotherapies that can act as “life-saver” medications to counteract the neurotoxic effects of synthetic cannabinoids (SCs). Towards this goal, we will synthesize CB1R antagonists with fast-onsets of action that can be administered in an emergency room (ER) situation. The rationale is based on the successful soft-agonist controlled deactivation approach developed at the Northeastern University’s (NEU) Center for Drug Discovery (CDD). The newly discovered ligands will be devoid of the undesirable effects caused by known CB1 inverse-agonists due to their ability to undergo rapid deactivation into inactive metabolites. Given that patients’ drug histories may not be known at admission, a key desired characteristic of the proposed antagonists as compared to the well-studied CB1 inverse agonist rimonabant (SR) is that they do not induce prolonged withdrawal reactions. First-generation SCs act as full CB1R agonists, mimic the “marijuana high” effects of Δ9-tetrahydrocannabinol (Δ9-THC), and exert their psychotropic effects with increased CB1 potency via CB1R activation. SCs are illegally sold as “designer drugs” and their consumption can be fatal unlike Δ9-THC which is a partial agonist and is less toxic. Lately, there has been a dramatic increase in SC related visits to emergency rooms and calls to poison control centers across the USA. Aim 1 will focus on the design and synthesis of novel controlled deactivation CB1R antagonists by utilizing the human CB1R (hCB1) crystal structure that was recently determined by our group. The design encompasses prototypes that have helped establish proof-of-concept. Aim 2 will focus on the in vitro characterization of ligands to determine their hCB1 affinity, hCB1/hCB2 selectivity, functional behavior, and stability. Aim 3 will focus on identifying brain penetrant compounds wherein ligands will be tested for CB1 antagonism and for their side-effects using procedures that are highly reproducible in mice of both genders. Fulfilling Phase I goals will further establish proof-of-concept for providing such treatment and for identifying advanced druggable leads. The project will help transition the most successful compounds towards Phase II for further optimization and pre-clinical evaluation aimed at obtaining one candidate and 2-3 back-ups. The next phase of this grant will focus on testing the optimized leads in validated pre-clinical rodent models of SC induced neurotoxicity using established behavioral paradigms that are considered perfect translational models to humans. Phase II/III development of the most favorable compounds will aim towards IND-enabling studies while partnering with industry.

项目概要/摘要 为了响应 PA-17-303，该第一阶段 STTR 提案将旨在开发可发挥作用的药物疗法 作为“救命”药物来抵消合成大麻素（SC）的神经毒性作用。 我们的目标是合成可在紧急情况下快速起效的 CB1R 拮抗剂 其原理基于成功的软激动剂控制失活方法。 由东北大学（NEU）药物发现中心（CDD）开发的新发现。 配体不会产生由已知 CB1 反向激动剂引起的不良影响，因为它们能够 鉴于患者的用药史可能不为人所知，因此会快速失活为无活性的代谢物。 与经过充分研究的 CB1 相比，所提出的拮抗剂的一个关键期望特征 第一代反向激动剂利莫那班（SR）的优点是它们不会引起长时间的戒断反应。 SC 充当完全 CB1R 激动剂，模仿 Δ9-四氢大麻酚 (Δ9-THC) 的“大麻高”效应，并且 SC 被非法出售 “设计药物”及其消耗可能是致命的，与 Δ9-THC 不同，Δ9-THC 是部分激动剂，毒性较小。 最近，与 SC 相关的急诊室就诊和中毒控制电话急剧增加 目标 1 将专注于新型受控失活 CB1R 的设计和合成。 利用我们小组最近确定的人类 CB1R (hCB1) 晶体结构来开发拮抗剂。 该设计包含有助于建立概念验证的原型，Aim 2 将重点关注内部。 配体的体外表征以确定其 hCB1 亲和力、hCB1/hCB2 选择性、功能行为、 目标 3 将侧重于识别脑渗透化合物，其中配体将进行 CB1 测试。 使用在两种性别的小鼠中都具有高度重现性的程序来研究其拮抗作用及其副作用。 实现第一阶段目标将进一步建立提供此类治疗和识别的概念验证 该项目将帮助最成功的化合物过渡到第二阶段。 进行进一步优化和临床前评估，旨在获得一名候选者和 2-3 名备份。 这笔资助的下一阶段将侧重于在经过验证的 SC 临床前啮齿动物模型中测试优化的引线 使用被认为是完美转化模型的既定行为范式诱导神经毒性 对人类最有利的化合物的 II/III 期开发将旨在支持 IND 研究。 同时与行业合作。