Preclinical Evaluation of GluR2-3Y Peptide as a Potential New Medication for Poly

药物滥用和成瘾在经济和社会成本以及人类个体成本方面对北美社会造成了巨大的损失。迫切需要有效的药物来治疗成瘾。尽管药物开发已经针对某些类型的成瘾（即阿片类药物成瘾）取得了进展，但这些药物具有显著的缺点。目前还没有批准的治疗许多类型的成瘾，如甲基苯丙胺或可卡因成瘾。使问题更加复杂的是，许多成瘾程度很高的边缘化人口也有很高程度的多种药物成瘾，也就是说，这些人口中的许多人经常使用多种药物并对多种药物成瘾。由于每种类型成瘾的潜在机制不同，因此针对这些个人和人群的治疗策略很复杂。针对不同类型成瘾的共同机制的创新策略可能对治疗这种多种药物成瘾非常有益，此外还可用于治疗单一物质成瘾。不列颠哥伦比亚省大学的研究人员已经开发出一种有前途的先导化合物，作为一种潜在的成瘾治疗方法。这种肽化合物不直接靶向药物受体，而是靶向成瘾行为背后的关联和学习机制。这些学习和联想机制已被证明对成瘾的渴望和复发方面都至关重要，并且与药物使用的奖励方面无关。该研究项目的长期目标是使用先导肽化合物进行人体临床试验，初始目标人群为注射吸毒者，其中至少一部分此类吸毒者对多种物质成瘾。因此，本文提出的短期目标是进行额外的非临床实验，以将该项目定位为后续正式的临床前安全性和毒性项目，以便快速进行FDA研究性新药申请和/或加拿大卫生部临床试验申请。研究建议中描述的实验包括在多种药物成瘾的动物模型中进一步测试先导化合物;确定先导化合物的最低有效剂量、最大耐受剂量、治疗指数和最佳剂量;在动物模型中完整的先导化合物药代动力学和生物分布特征;以及研究鼻内给药的替代模式，以潜在地扩大将该化合物用于更广泛的目标人群的适用性和可行性。

DESCRIPTION (provided by applicant): Substance abuse and addiction represents a huge drain on North American society, in terms of economic and social costs, as well as the human individual cost. The need for effective medications to treat addiction is urgent. Although medications development has progressed for certain types of addiction, namely opioid addiction, these medications have significant drawbacks. There remain no currently approved therapies for many types of addiction such as methamphetamine or cocaine addiction. Further complicating matters is that many marginalized populations suffering from high levels of addiction also have very high levels of polydrug addiction that is, many individuals in these populations regularly use and are addicted to multiple substances. Treatment strategies for such individuals and populations are complex due to the various mechanisms underlying each type of addiction. Innovative strategies that target mechanisms common to different types of addiction may be of great benefit in treating such polydrug addictions, in addition to also be useful for treating single substance addictions. Researchers at The University of British Columbia have developed a promising lead compound as a potential addiction therapy. This peptide compound does not directly target drug receptors, but rather targets the association and learning mechanisms underlying addiction behaviors. These learning and association mechanisms have been shown to be critical for both the craving and the relapse aspects of addiction, and are not related to the reward aspects of drug use. It is a long range goal of the research project to conduct a human clinical trial using the lead peptide compound, with an initial target population of injection drug users where at least a portion of such drug users are addicted to multiple substances. Thus the short term goals proposed herein are to perform additional non-clinical experiments to position the project for a follow-on formal preclinical safety and toxicity program, in order to proceed quickly towards an FDA Investigational New Drug Application and/or Health Canada Clinical Trial Application. The experiments described in the research proposal include further testing of the lead compound in an animal model of polydrug addiction; determination of minimum efficacy dose, maximum tolerated dose, therapeutic index, and optimal dose of the lead compounds; full pharmacokinetic and biodistribution profiling of the lead compound in animal model; and investigation of an alternate mode of delivery, intranasal, to potential expand the applicability and feasibility of using the compound with a broader target population.