Optimization of Allosteric Modulators of 5-HT2C Receptor

描述（由申请人提供）：5-HT2C受体（5-HT2CR）功能的调节在治疗严重未满足医疗需求的疾病方面具有巨大的治疗前景，包括成瘾，焦虑，抑郁，肥胖/饮食失调和精神分裂症。5-HT2CR配体的成功开发需要对高度同源的5-HT2AR和5-HT2BR具有选择性，因为这些受体的激动作用可导致严重的中枢神经系统和心血管不良事件。该建议的基本原理是，5-HT2CR的变构调节剂提供了一种独特的药物设计策略，以位点和事件特异性的方式增强对内源性5-HT的反应。这种利用5-HT2CR的变构调节剂开发新型探针和治疗方法的新方法非常有吸引力，因为与变构位点结合的配体比与内源性配体结合的正构配体更容易实现高受体亚型选择性甚至绝对特异性。迄今为止，通过化合物文库筛选，只有一个化合物PNU-69176E被鉴定为5-HT2CR变构调制剂。然而，相关的构效关系（SAR）研究较少，因此我们在这方面的知识相当有限。我们的目标是优化和开发5-HT2CR的变张力调节剂，以产生新的、高选择性的、有效的5-HT2CR配体，作为神经系统的小分子探针和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化学合成与优化；2)利用基于细胞的信号分析方法对新合成的化合物进行生物学表征，以鉴定具有高效、选择性和更好的药物样性质的5-HT2CR变构调节剂。该项目具有创新性，具有潜在的高影响力，将有助于阐明5-HT2CR变构调节的化学神经生物学信息。我们的研究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和新的机制见解。拟议的研究将确定小分子，将用于探测5-HT2CR的神经生物学。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化研究中的临床应用，并最终作为新的治疗候选药物。

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.