New Opioids for Alcoholism

描述(申请人提供)：用于治疗酒精中毒的高效力、口服活性、代谢稳定、长寿的阿片类药物，这些药物减少了副作用，如恶心、成瘾倾向、免疫抑制和呼吸抑制，这是一个巨大的未得到满足的需求。尽管一种Mu阿片受体拮抗剂目前被FDA批准用于治疗酒精中毒，但它有几个缺点。最近，人类临床试验表明，一种新的阿片类药物可以改善副作用。在这项第一阶段的提案中，这些专门设计为Mu阿片受体拮抗剂的新型阿片类药物的有效同系物将通过药物化学进行优化，并在体外和体内进行药理活性测试。本文为第一阶段提出的药物化学将导致先前确定的最有效候选药物的额外线索优化。这项建议的目的包括：1)在动物模型中测试目前可用的新型阿片类拮抗剂减少酒精消耗的可行性，2)优化药理活性，3)最有希望的候选药物的临床前安全性最大化。在这项工作成功完成后，在第二阶段将对候选药物进行更广泛的动物测试。我们可行性工作的目标是证明基于我们的体外数据可以在动物模型中观察到有效和安全的药物。我们期待所提出的新型解酒药物候选药物的开发将为未来改善人类痛苦和经济损失提供新的药物。戒酒药物，动物模型，药物开发，阿片类药物评价。迫切需要有效的、口服活跃的、代谢稳定的、长寿的药物来解决酒精滥用问题。购买一种副作用比目前使用的药物更好的长效口服戒酒药物将提供一种目前无法获得的治疗方法。这项工作的潜在商业应用是，这项研究可能会导致一种“重磅炸弹”的药物产品。

DESCRIPTION (provided by applicant): Highly potent, orally active, metabolically stable, long-lived opioid agents for the treatment of alcoholism that have decreased side effects such as nausea, addiction liability, immunosuppression and respiratory depression represents a great unmet need. While a mu opioid receptor antagonist is currently approved by the FDA for alcoholism, it possesses several drawbacks. Recently, human clinical trials have shown that a new class of opioid with an improved side effect profile is available. In this Phase I proposal, efficacious congeners of these novel opioids specifically designed to be antagonists of the mu opioid receptor will be optimized by medicinal chemistry and tested in vitro and in vivo for pharmacological activity. Medicinal chemistry proposed herein for Phase I will lead to additional lead optimization of the most efficacious drug candidates identified previously. The Aims of this proposal include: 1) Test the feasibility of the currently available novel opioid antagonists to decrease alcohol consumption in an animal model, 2) Optimize the pharmacological activity and 3) Maximize the preclinical safety of the most promising drug candidates. After the successful completion of this work, more extensive testing of drug candidate compounds will be done in animals in Phase II. The goal of our feasibility work is to show that efficacious and safe agents can be observed in animal models based on our in vitro data. We expect that development of the proposed novel anti-alcoholism drug candidates will provide new agents useful in the future amelioration of human suffering and economical loss. Anti-alcoholism medication, animal models, drug development, opioid drug evaluation. The need for potent, orally active, metabolically stable, long-lived medication to address alcohol abuse is immense. Procurement of a long-lasting oral anti-alcoholism medication that has an improved side effect profile compared with agents currently in use will provide a therapeutic that is currently not available. The potential commercial application of the work is that the research could lead to a 'blockbuster' drug product.