Optimization of Allosteric Modulators of 5-HT2C Receptor

描述(申请人提供)：5-HT2C受体(5-HT2CR)功能的调节具有巨大的治疗前景，可用于治疗未得到满足的重大医学需求的疾病，包括成瘾、焦虑、抑郁、肥胖/饮食障碍和精神分裂症。5-HT2CR配体的成功开发需要相对于高度同源的5-HT2AR和5-HT2BR的选择性，因为这些受体的激动会导致严重的中枢神经系统和心血管不良事件。这一建议的基本原理是，5-HT2CR的变构调节剂提供了一种独特的药物设计策略，以特定部位和事件的方式增强对内源性5-羟色胺的反应。这种利用5-HT2CR的变构调节剂来开发新的探针和治疗药物的新方法非常有吸引力，因为与内源配体结合的配体相比，通过与变构位点结合的配体更容易获得高的受体亚型选择性甚至绝对专一性。到目前为止，只有一种化合物PNU-69176E通过化合物文库筛选被鉴定为5-HT2CR变构调节剂。然而，相关的构效关系(SAR)研究很少，因此我们在这方面的知识相当有限。我们在这一应用中的目标是优化和开发5-HT2CR的变构调节剂，以产生新的、高选择性和有效的5-HT2CR配体，这些配体将作为神经系统的小分子探针和治疗中枢神经系统疾病的新疗法。为了实现这一目标，我们计划追求以下两个具体目标：1)以PNU-69176E为化学先导的小分子的化学合成和优化；以及2)新合成的化合物的生物学表征，使用基于细胞的信号分析来确定具有高效、选择性和更好的类药物性质的5-HT2CR的变构调节剂。这个项目是创新的，潜在的高影响研究，将有助于阐明5-HT2CR变构调节的化学神经生物学信息。我们的结果有望为这些化学上独特的5-HT2CR变构调节剂提供有价值的SAR和新的机制洞察。拟议的研究将确定将被用于探索5-HT2CR的神经生物学的小分子。该项目的长期目标是开发这些调节剂，用于临床前验证和转译研究的临床应用，并最终成为新的候选治疗药物。 公共卫生相关性：这项研究项目与公共卫生高度相关，因为它涉及5-HT2C受体的新型变构调节剂的化学合成、优化和药理学研究，这些调节剂将作为神经系统的小分子探针，并针对各种重大未得到满足的医疗需求的中枢神经系统疾病提供新的治疗方法。因此，拟议的研究与NIH任务的一部分有关，该部分涉及开发有助于延长寿命和减轻疾病负担的新药和基础知识。

DESCRIPTION (provided by applicant): The modulation of 5-HT2C receptor (5-HT2CR) function holds a tremendous amount of therapeutic promise for the treatment of diseases of significant unmet medical need, including addiction, anxiety, depression, obesity/eating disorders and schizophrenia. Successful development of 5-HT2CR ligands requires selectivity versus the highly homologous 5-HT2AR and 5-HT2BR, because agonism at these receptors can result in serious CNS and cardiovascular adverse events. The rationale for this proposal is that allosteric modulators of the 5-HT2CR present a unique drug design strategy to augment the response to endogenous 5-HT in a site- and event-specific manner. This novel approach of using allosteric modulators of the 5-HT2CR to develop novel probes and therapeutics is very attractive since it is much easier to achieve high receptor subtype selectivity or even absolute specificity with a ligand binding to the allosteric site than with orthosteric ligands that bind to the endogenous ligand binding site. To date only one compound, PNU-69176E, has been identified via the compound library screening as a 5-HT2CR allosteric modulator. However, the relevant structure-activity relationship (SAR) studies were sparse, and thus our knowledge in this regard is quite limited. Our objective in this application is to optimize and develop allosteric modulators of the 5-HT2CR to generate novel, highly selective and potent 5-HT2CR ligands that will act as small molecule probes for the nervous system and novel therapeutics for CNS disorders. To accomplish this objective, we plan to pursue the following two specific aims: 1) Chemical synthesis and optimization of small molecules based on PNU-69176E as the chemical lead; and 2) Biological characterization of newly synthesized compounds using a cell-based signaling assay to identify allosteric modulators of 5-HT2CR with high potency, selectivity and better drug-like properties. This project is innovative, potentially high impact research that will aid in elucidating information about the chemical neurobiology of allosteric modulation of 5-HT2CR. Our results are expected to provide the valuable SAR and novel mechanistic insight into these chemically unique allosteric modulators of 5-HT2CR.The proposed studies will identify small molecules that will be utilized to probe the neurobiology of the 5-HT2CR. The long term goal of this project is to develop these modulators for preclinical validation and clinical application in translational research and ultimately as novel therapeutic candidates. PUBLIC HEALTH RELEVANCE: This research project is highly relevant to public health because it entails chemical synthesis, optimization and pharmacological investigation of novel allosteric modulators of the 5-HT2C receptor that will act as small molecule probes for nervous system and novel therapeutics for a variety of CNS disorders of significant unmet medical need. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing new medications and fundamental knowledge that will help to lengthen life and to reduce the burdens of illness.