Small Molecule Libraries Targeted to CBP and Attenuation AfosB Expression

成瘾是一种慢性、复发性精神障碍，其特征是强迫性寻求毒品。 对涉案个人造成重大身体、精神和社会伤害的行为。进展 已经在阐明成瘾发生的潜在神经适应方面取得了进展。这些措施包括： 在某种程度上，颠覆或劫持正常神经元可塑性与奖赏、记忆和 学习。细胞对外界刺激的反应方式之一，包括病理刺激，如 滥用精神刺激剂，是通过改变其基因表达模式和一种机制来实现的 是通过表观遗传变化导致基因转录模式改变。感应？FosB是一口井 表征了与长期服用这些药物有关的神经整形事件。 暴露在滥用的精神刺激剂中，例如可卡因，会导致基因的组蛋白乙酰化 包括FosB在内的早期反应基因的启动子以及随后的转录激活。 FosB启动子乙酰化的增加已被证明依赖于CBP(CREB结合 蛋白质)依赖组蛋白乙酰转移酶(HAT)活性。因此，接触滥用药物的情况如下 可卡因和苯丙胺被证明能增加FosB蛋白的表达 伏隔核。在慢性治疗方面，FosB的一种寿命更长的截断剪接变体， FosB在神经元中表达，并随着向成瘾状态的转变而积累。 FosB在停药后存在较长一段时间，因此 作为长期成瘾行为形成的诱因，因此 故态复萌。这项拟议的研究要检验的关键生物学假设是 小分子抑制剂对CBP活性的减弱将减少CBP的乙酰化 FosB基因启动子，进而降低FosB和FosB蛋白的表达。 西奈山化学图书馆的高通量筛查发现了两个系列的热门 与CBP溴域结合的分子。此外，这些命中已被证明抑制 CBP在基于细胞的报告分析中介导HAT活性。这些化学铅系列是可接受的。 通过平行合成技术探索和精制以创建CBP抑制剂的文库。 这项提议的广泛主题是通过有针对性的文库合成和 药物化学提供将抑制FosB诱导的小分子 CBP HAT活性的衰减。这些小分子将作为药理工具发挥作用 研究向成瘾状态转变中潜在的神经元适应，并可能提供 预防或逆转成瘾的新治疗方法。

Addiction is a chronic, relapsing psychiatric disorder characterized by compulsive drug seeking behaviors despite significant physical, mental and social harm to the individuals involved. Progress has been made in elucidating the underlying neuroadaptions that occur in addiction. These involve, in part, a subversion, or hijacking of normal neuronal plasticity associated reward, memory and learning. One of the ways cells respond to external stimuli, including pathological stimuli such as abused psychostimulants, is by altering their pattern of gene expression and one mechanism for this is via epigenetic changes leading to altered patterns of gene transcription. Induction ¿FosB is a well characterized neuroplastic event associated with chronic administration of these drugs. Exposure to abused psycostimulants, for example cocaine, leads to histone acetylation of gene promoters, and consequent transcriptional activation, of early response genes, including FosB. Increase in FosB promoter acetylation has been shown to be dependant on CBP (CREB binding protein) dependant histone acetyl transferase (HAT) activity. Thus exposure to drugs of abuse such cocaine and amphetamines have been shown to lead to increase FosB protein expression in cells of the nucleus accumbens. On chronic treatment, a longer lived truncated splice variant of FosB, ¿FosB, is expressed and this accumulates in neurons as the transition to an addicted state occurs. ¿FosB is present for an extended period of time after drug is withdrawn and it has thus been implicated as a causative agent in the formation of longer term addictive behaviors and hence propensity for relapse. The key biological hypothesis to be tested by the proposed research is that attenuation of CBP activity by a small molecule inhibitor will reduce acetylation of the FosB gene promoter, which in turn will lower FosB and ¿FosB protein expression. High throughput screens of chemical libraries at Mount Sinai have identified two series of hit molecules in a binding assay to CBP bromodomain. Further, these hits have been shown to inhibit CBP mediated HAT activity in cell based reporter assays. These chemical lead series are amenable to exploration and elaboration by parallel synthesis techniques to create libraries of CBP inhibitors. The broad theme of this proposal is to optimize these hits via targeted library synthesis and medicinal chemistry to provide small molecules which will inhibit ¿FosB induction via attenuation of CBP HAT activity. These small molecules will function as pharmacological tools to investigate the underlying neuronal adaptations in transition to the addicted state and may provide a novel therapeutic modality for the prevention or reversal of addiction.