Medications for Synthetic Cannabinoid Abuse

项目总结/摘要 作为对PA-17-303的回应，该I期STTR提案旨在开发可发挥作用的药物疗法。 作为“救生”药物，以抵消合成大麻素（SC）的神经毒性作用。为实现这一 我们的目标是，我们将合成具有快速起效作用的CB 1 R拮抗剂，可在紧急情况下使用 房间（ER）的情况。基本原理是基于成功的软激动剂控制失活方法 东北大学（NEU）药物发现中心（CDD）开发的。新发现的 配体将没有由已知的CB 1反向激动剂引起的不希望的作用， 迅速失活为无活性代谢物。考虑到患者的用药史可能不为人知， 与研究充分的CB 1相比， 反向激动剂利莫那班（SR）的另一个优点是它们不诱导长时间的戒断反应。一代 SC作为完全CB 1 R激动剂，模拟Δ9-四氢大麻酚（Δ9-THC）的“大麻高”效应， 通过CB 1 R活化增加CB 1效力来发挥其精神作用。SC被非法出售， “设计药物”和它们的消费可能是致命的，不像Δ9-THC，Δ 9-THC是一种部分激动剂，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 美国各地的中心。目的一是设计合成新型可控失活化合物CB 1 R 拮抗剂通过利用人类CB 1 R（hCB 1）的晶体结构，最近确定了我们的小组。 该设计包括帮助建立概念验证的原型。目标2将侧重于 体外表征配体以确定它们的hCB 1亲和力、hCB 1/hCB 2选择性、功能行为， 与稳定目标3将集中于鉴定脑渗透剂化合物，其中将测试配体的CB 1 使用在两种性别的小鼠中高度可重复的程序来评估它们的拮抗作用和副作用。 实现第一阶段的目标将进一步建立提供这种治疗的概念验证， 先进的可下药的线索该项目将帮助最成功的化合物过渡到第二阶段 用于进一步优化和临床前评价，旨在获得一个候选和2-3个备份。的 该资助的下一阶段将重点在经验证的SC临床前啮齿动物模型中测试优化的线索 使用被认为是完美转化模型的既定行为范例诱导神经毒性 对人类最有利化合物的II/III期开发将致力于IND使能研究 同时与工业界合作。

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.