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、依赖（成瘾）和戒断期间复发的脆弱性是美国主要的公共卫生问题，需要有效、安全的药物治疗方法。5-HT2CR受体（5-HT2CR）已被确定为精神兴奋剂行为效应的重要中介，选择性5-HT2CR激动剂在抑制兴奋剂的鉴别刺激效应以及自我给药模型中的药物服用和药物寻求方面显示出疗效。因此，通过5-HT2CR最大化信号传导的策略可能被证明对抑制兴奋剂滥用者复发有治疗作用。最近发现5-HT2CR的细胞内第3环结合10号染色体上缺失的蛋白磷酸酶和紧张素同源物来控制受体的激活状态，这为新的药物开发提供了机会。5-HT2CR:PTEN复合物被5-HT2CR的一个小肽片段破坏，该片段在体内唤起5-HT2CR激动剂样特性，且副作用有限，这表明抑制5-HT2CR:PTEN结合的脑渗透肽或小分子将是增强5-HT2CR功能的新方法。在响应RFA-DA-10-018提交的本提案中，我们将使用多学科方法研究5-HT2CR:PTEN关联作为一种新的药理学靶点，包括化学、分子模型、体外活细胞实验和体内成瘾的临床前模型。我们将基于模拟的5-HT2CR和PTEN之间的肽界面，设计和合成新的5-HT2CR:PTEN相互作用的肽和拟肽抑制剂，并将其转化为具有高活性和类药物性质的优化小分子。这些新型抑制剂将在活细胞试验中评估其破坏5-HT2CR:PTEN复合物并通过5-HT2CR增强信号传导的功效。优化后的5- HT2CR:PTEN相互作用抑制剂的效价、疗效和选择性将通过大鼠药物鉴别模型在体内进行评估。最有希望的候选人将在可卡因自我给药和恢复试验中进行评估。这些研究将提供新的多肽、小分子和细胞分析方法来探索5-HT2CR大分子复合物的神经生物学功能，并有可能发现治疗人类精神兴奋剂成瘾的新药物。

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.