Medications for Synthetic Cannabinoid Abuse

项目摘要/摘要 作为对PA-17-303的响应，这项第一阶段STTR提案将旨在开发能够起作用的药物疗法 作为“救命药”来对抗合成大麻素(SCs)的神经毒性。朝向这个方向 目标，我们将合成CB1R拮抗剂，具有可在紧急情况下使用的快速动作集 房间(ER)情况。其基本原理是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。新发现的 配体将不会有已知的CB1反向激动剂引起的不良影响，因为它们有能力 迅速失活为不活跃的代谢物。考虑到患者的吸毒史可能不会在 与经过充分研究的CB1相比，入院是建议的拮抗剂的一个关键期望特征 反向激动剂利莫那班(SR)不会引起长时间的戒断反应。第一代 SCs作为完整的CB1R激动剂，模拟Δ9-四氢大麻酚(Δ9-THC)的“大麻兴奋”效应，以及 通过激活CB1R，通过增强CB1的效力来发挥其精神药物作用。SCS被非法出售为 “特制药物”及其消费可能是致命的，不像Δ9-THC，后者是部分激动剂，毒性较低。 最近，与SC相关的急诊室就诊和毒物控制电话大幅增加 中心遍布全美。目标1将重点设计和合成新型受控失活CB1R 利用本课题组最近确定的人CB1R(HCB1)晶体结构。 该设计包含了帮助建立概念验证的原型。Aim 2将专注于In 体外表征配体以确定其hCB1亲和力、hCB1/hCB2选择性、功能行为 和稳定性。目标3将专注于识别大脑渗透化合物，其中配体将接受CB1测试 使用在不同性别的小鼠身上高度可重现的程序来对抗和它们的副作用。 实现第一阶段目标将进一步建立概念验证，以提供此类治疗并确定 先进的可下药线索。该项目将帮助将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估，旨在获得一个候选和2-3个后备。这个 这笔赠款的下一阶段将专注于在经过验证的SC临床前啮齿动物模型中测试优化的线索 使用被认为是完美翻译模型的已建立的行为范式来诱导神经毒性 对人类来说。第二阶段/第三阶段开发最有利的化合物将着眼于促进Ind的研究 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.