Cannabinergic Receptor Antagonists for Nicotine Addiction

描述（由申请人提供）：动物和人的现有证据表明，阻断CB1受体可能是对抗尼古丁成瘾的有效方法。早期对人类的研究已经记录了这些影响。该I期申请旨在设计先进的CB1吡咯烷酮拮抗剂，以开发戒烟药物。我们的目的是：1)开发具有有限的反向激动剂或中性拮抗剂活性的CB1拮抗剂，2)在大鼠行为筛查试验中表征它们减弱尼古丁影响的能力，这些测试可以在I期项目的限制内进行。我们期望将最成功的化合物从I期研究推进到II期研究，在II期研究中，我们将追求更详细的先导优化程序，表征化合物的副作用，并评估它们在非人类灵长类动物中建立的与成瘾相关的自我给药研究中减少尼古丁成瘾相关影响的能力。这样的II期研究应该有一个临床前候选药物和2-3个备用药物。

DESCRIPTION (provided by applicant): Existing evidence in animals and man indicates that blockade of the CB1 receptor may offer an effective approach for combating nicotine addiction. Early studies in humans have documented these effects. This Phase I application proposes studies to design advanced CB1 pyrrolidinone antagonists toward the development of medications for smoking cessation. Our intention is to: 1) develop CB1 antagonists with limited inverse agonist or neutral antagonist activity and 2) to characterize their ability to attenuate th effects of nicotine in behavioral screening assays in rats that can be conducted within the limits of a Phase I program. We expect to forward the most successful compounds from Phase I into Phase II studies, in which we shall pursue a more detailed lead optimization program, characterize compounds for side-effect liability, and evaluate their ability to reduce addiction-related effects of nicotine in established, addiction-related, self- administration studies in nonhuman primates. Such Phase II studies should lead to one pre-clinical candidate and 2-3 back-ups.