ANALOGS OF METHYLLYCACONITINE--SELECTIVE NICOTINIC AGENT

描述：(申请人摘要) 我们发现了一种简单的甲基乌头碱类似物(MLA)，它可以作为一种 烟碱型乙酰胆碱受体微摩尔抑制物(NAChR)。这 应该是一个肥沃的地区，从中可以找到有选择性的和强有力的敌手 NAChR的亚型。这项建议的目标是快速勾勒出一个特别行政区的轮廓 (构效关系)，以评估这种新的先导化合物 效力和选择性所必需的结构要求。这将导致 新的药理工具以及帮助开发新的nAChR 拮抗剂就像毒品一样。 通过对取代基上的氮基进行系统的评价 以及对哌啶环本身的改变，我们将 根据效价和受体亚型确定最佳基团 专一性。我们还将制备不同取代的亚胺，以便 根据效价和受体亚型确定最佳位置 专一性。所有类似物都将根据效力和 受体亚型特异性。 MLA是一种非常有趣的新开发的先导化合物 NAChR拮抗剂。MLA是最有效的非肽nAChR拮抗剂 目前已知的。由于来自自然来源的MLA的可用性是有限的， 关于了解工作重点特别行政区的工作还很少报道。而当 已经合成了几个MLA的类似物，只有少数生物学报道 活动已经发表。这些以前的类比未能完全 定义MLA的药效团。 我们描述了一系列的类比，这将使我们能够开发出详细的 烟碱拮抗剂MLA的药效团。我们的类比是新奇的，迅速的 准备，并针对工作重点的两个最重要的部分进行研究。这些 主要的结构特征将使我们能够迅速达成一项详细的 MLA的药效团。这些研究有可能成为第一步 未来在设计和发现新型尼古丁方面的广泛工作 探员们。这些类型的化合物具有潜在的药理作用 并有助于理解和治疗尼古丁成瘾。

DESCRIPTION: (Applicant's Abstract) We have discovered a simple analog of methyllycaconitine (MLA) that acts as a micromolar inhibitor at the nicotinic acetylcholine receptor nAChR). This should be a fertile area from which to find selective and potent antagonists of subtypes of the nAChR. The goal of this proposal is to quickly outline an SAR (Structure Activity Relationship) of this new lead compound in order to assess structural requirements necessary for potency and selectivity. This will lead to new pharmacological tools as well as aid in the development of novel nAChR antagonists as drugs. Through a systematic evaluation of substituents on the nitrogen of the piperidine ring as well as alterations to the piperidine ring itself, we will determine an optimal group with regard to potency and receptor subtype specificity. We will also prepare differently substituted imides in order to determine the optimal placement with regard to potency and receptor subtype specificity. All analogs will be evaluated with regard to the potency and receptor subtype specificity. MLA is extremely interesting as a lead compound for the development of new nAChR antagonists. MLA is the most potent non-peptide nAChR antagonist currently known. Since the availability of MLA from natural sources is limited, very little work on understanding the SAR of MLA has been reported. While several analogs of MLA have been synthesized only a few reports of biological activity have been published. These previous analogs have failed to fully define the pharmacophore of MLA. We describe a series of analogs that will allow us to develop a detailed pharmacophore of the nicotinic antagonist MLA. Our analogs are novel, rapidly prepared, and target the two most significant portions of MLA for study. These key structural features will allow us to expeditiously arrive at a detailed pharmacophore for MLA. These studies have the potential to be the first step for extensive future work on the design and discovery of novel nicotinic agents. These types of compounds have potential use as pharmacological tools and aids in understanding and treating nicotine addiction.