Inhibitors of 5-HT2CR Protein:Protein Interactions for Stimulant Pharmacotherapy

描述（由申请人提供）：精神兴奋剂滥用和依赖（成瘾）的脆弱性以及戒断期间的复发是美国的主要公共卫生问题，需要有效、安全的药物治疗方法。5-HT 2CR受体（5-HT 2CR）已被确定为精神兴奋剂的行为效应的重要介质，并且选择性5-HT 2CR激动剂已显示出抑制兴奋剂的辨别性刺激效应以及自我给药模型中的药物服用和药物寻求的功效。因此，通过5-HT 2CR最大化信号传导的策略可能证明在抑制兴奋剂滥用者的复发方面具有治疗作用。最近发现5-HT 2CR的第3胞内环结合10号染色体上缺失的蛋白磷酸酶和张力蛋白同源物以控制受体的激活状态，这提供了新的药物开发机会。5-HT 2CR：PTEN复合物被5-HT 2CR的小肽片段破坏，其在体内引起5-HT 2CR激动剂样性质，具有有限的副作用特征，这表明抑制5-HT 2CR：PTEN缔合的脑渗透肽或小分子将是增强5-HT 2CR功能的新方法。在响应RFA-DA-10-018提交的本提案中，我们将使用涉及化学、分子建模、体外活细胞测定和体内成瘾临床前模型的多学科方法，将5-HT 2CR：PTEN关联作为一种新型药理学靶点进行研究。我们将基于5-HT 2CR和PTEN之间的模拟肽界面设计和合成新的5-HT 2CR：PTEN相互作用的肽和肽模拟物抑制剂，并将其转化为高活性和药物样性质的优化小分子。这些新型抑制剂将在活细胞测定中评估其破坏5-HT 2CR：PTEN复合物和增强通过5-HT 2CR的信号传导的功效。将使用大鼠药物辨别模型在体内评估5-HT 2CR：PTEN相互作用的优化抑制剂的效力、功效和选择性。最有希望的候选人将在可卡因自我管理和恢复分析进行评价。拟议的研究将提供新的肽，小分子和细胞测定，以探测5-HT 2CR大分子复合物的神经生物学功能，并可能发现用于治疗人类精神兴奋剂成瘾的新型治疗药物。 公共卫生相关性：需要新的、有效的和可获得的治疗兴奋剂成瘾的方法，以减轻药物滥用障碍的慢性心理和身体负担。通过一个包括化学，细胞生物学和行为学的多学科项目，我们将开发新的肽和药物，以探索和验证成瘾的新大脑靶点。这些化合物和这里开发的新检测方法将使我们能够探测大脑的生物学，以创造新的方法来增强兴奋剂依赖者的禁欲。

DESCRIPTION (provided by applicant): Psychostimulant abuse and vulnerability to dependence (addiction) and relapse during abstinence linger as major public health problems in the United States and effective, safe pharmacotherapeutic approaches are needed. The 5-HT2CR receptor (5-HT2CR) has been identified as an important mediator of the behavioral effects of psychostimulants and selective 5-HT2CR agonists have shown efficacy in suppression of the discriminative stimulus effects of stimulants as well as drug-taking and drug-seeking in self-administration models. Thus, strategies to maximize signaling through the 5-HT2CR may prove therapeutically useful to inhibit relapse in stimulant abusers. The recent discovery that the 3rd intracellular loop of the 5-HT2CR binds protein phosphatase and tensin homologue deleted on chromosome 10 to control activation states of the receptor provides a new medication development opportunity. The 5- HT2CR:PTEN complex is disrupted by a small peptide fragment of the 5-HT2CR which evokes 5- HT2CR agonist-like properties in vivo with a limited side effect profile, suggesting that either brain-penetrant peptides or small molecules that inhibit the 5-HT2CR:PTEN association will be a novel method to enhance 5-HT2CR function. In the present proposal, submitted in response to RFA-DA-10-018, we will examine the 5-HT2CR:PTEN association as a novel pharmacological target using a multidisciplinary approach involving chemistry, molecular modeling, live cell assays in vitro and preclinical models of addiction in vivo. We will design and synthesize new peptide and peptidomimetic inhibitors of the 5-HT2CR:PTEN interaction based on the modeled peptide interface between the 5-HT2CR and PTEN, and convert these into small molecules optimized for high activity and drug-like properties. These novel inhibitors will be evaluated in live cell assays for their efficacy to disrupt the 5-HT2CR:PTEN complex and enhance signaling through the 5-HT2CR. The potency, efficacy and selectivity of optimized inhibitors of the 5- HT2CR:PTEN interaction will be assessed in vivo in using rat drug discrimination models. The most promising candidates will be evaluated in cocaine self-administration and reinstatement assays. The proposed studies will provide novel peptides, small molecules and cellular assays to probe the neurobiological function of the 5-HT2CR macromolecular complex and potentially discover novel therapeutic agents for the treatment of psychostimulant addiction in humans. PUBLIC HEALTH RELEVANCE: New, effective and accessible modalities for the treatment of stimulant addiction are needed to alleviate the chronic, psychological and physical burdens of substance abuse disorders. Through a multidisciplinary project including chemistry, cell biology and behavior, we will develop new peptides and drugs to explore and validate a new brain target in addiction. These compounds and the new assays developed here will allow us to probe the biology of the brain to create new ways to enhance abstinence in stimulant-dependent individuals.