ANALOGS OF METHYLLYCACONITINE--SELECTIVE NICOTINIC AGENT

描述：（申请人摘要） 我们已经发现了一种简单的类似物甲基乌头碱（MLA）， 烟碱乙酰胆碱受体nAChR的微摩尔抑制剂）。这 应该是一个肥沃的领域，从中找到选择性和有效的拮抗剂， nAChR的亚型。该提案的目标是快速勾勒出一个特区 （结构活性关系），以评估 效力和选择性所必需的结构要求。这将导致 新的药理学工具，以及在新的nAChR的发展援助 拮抗剂作为药物。 通过系统地评价化合物的氮上的取代基， 哌啶环以及哌啶环本身的改变，我们将 根据效力和受体亚型确定最佳组 的特异性我们还将制备不同取代的酰亚胺， 根据效价和受体亚型确定最佳放置位置 的特异性将评价所有类似物的效力， 受体亚型特异性 MLA是非常有趣的作为一种先导化合物的发展新的 nAChR拮抗剂。MLA是最有效的非肽类nAChR拮抗剂 目前已知。由于从自然来源获得的司法协助有限， 据报告，在了解司法协助的SAR方面开展的工作很少。而 已经合成了MLA的几种类似物， 活动已经公布。这些以前的类似物未能完全 确定MLA的药效团。 我们描述了一系列类似物，这将使我们能够开发一个详细的 烟碱拮抗剂MLA的药效团。我们的类似物是新颖的， 准备，并针对MLA的两个最重要的部分进行研究。这些 关键的结构特征将使我们能够迅速达成详细的 MLA的药效团。这些研究有可能成为 用于设计和发现新型尼古丁的广泛未来工作 剂.这些类型的化合物具有作为药理学工具的潜在用途 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.