ANALOGUES OF METHYLLYCACONITINE

描述(申请人提供)：我们发现了一系列新的 生物碱甲基乌头碱(MLA)的类似物，在 神经型烟碱型乙酰胆碱受体(NAChR)。我们的目标是 提案是确定赋予尼古丁的MLA的结构方面 拮抗剂活性。我们的假设是，MLA类似物含有更多的 MLA结构(更类似于MLA)将更加有效和有选择性 α7nAChR的拮抗剂。我们的长期目标是了解 小分子烟碱受体结合和用途的结构决定因素 这一认识有助于设计和合成新型药物制剂。 我们建议根据MLA的结构制备新的类似物。这些 化合物将包括E环类似物以及含有 环C、B、D和F。这些新的类似物在 Apha7 nAChR.我们建议用改进的方法制备MLA的E环类似物 α3nAChR的效价。我们将评估其效力和受体亚型。 MLA类似物的特异性。类比活性和亚型特异性将是 通过使用模型系统的绑定和功能研究进行评估 CNS和外周nAChRs均有表达。 总而言之，我们发现了一个简单的MLA模拟，它应该在 评估效力和nAChR亚型所需的结构要求 选择性。我们已经制备了四个系列的MLA类似物，并对它们进行了检测 在字母7、字母3和字母4上既有效力又有选择性的化合物 NAChR。这些初步研究进一步确定了 哌啶环上的氮取代和取代 丁二酰亚胺环。我们已经建立了一种与α3 nAChR结合的分析方法 对我们的工作以及对烟碱配体的一般研究都是有用的 选择性。 在我们R03拨款的支持下，我们已经实现了最初的目标，展示了 我们可以制备和评估作为尼古丁的MLA类似物 对抗者。此外，我们还表明，这些化合物中有几个属于 已知最有效的尼古丁拮抗剂。我们还表明， 这些化合物的效力可以通过简单的修饰来提高。

DESCRIPTION (provided by applicant): We have discovered a new series of analogues of the alkaloid methyllycaconitine (MLA) that act as antagonists at the neuronal nicotinic acetylcholine receptor (nAChR). Our goals for this proposal are to determine the structural aspects of MLA that confer nicotinic antagonist activity. Our hypothesis is that MLA analogues incorporating more of the MLA structure ("more MLA-like") will be more potent and selective antagonists at the alpha7 nAChR. Our long-term goals are to understand the structural determinants of small molecule - nicotinic receptor binding and use this understanding to design and synthesize novel pharmaceutical agents. We propose to prepare novel analogues based upon the structure of MLA. These compounds will include ring E analogues as well as analogues incorporating rings C, B, D, and F. These new analogues should have excellent potency at the apha7 nAChR. We propose to prepare ring E analogues of MLA with improved potency at the alpha3 nAChR. We will evaluate the potency and receptor subtype specificity of MLA analogues. Analog activity and subtype specificity will be assessed through both binding and functional studies using model systems expressing both CNS and peripheral nAChRs. Overall, we have found a simple analogue of MLA that should be useful in assessing structural requirements necessary for potency and nAChR subtype selectivity. We have prepared four series of MLA analogues and assayed these compounds for both potency and selectivity at the alpha7, alpha3, and alpha4 nAChR. These preliminary studies further define the structural importance of substitution on the nitrogen of the piperidine ring and substitution on the succinimide ring. We have developed a binding assay for the alpha3 nAChR which should be useful for our work as well as the general study of nicotinic ligand selectivity. With the support of our R03 grant we have met our initial goals, demonstrating that we can both prepare and evaluate analogues of MLA as nicotinic antagonists. Further we have shown that several of these compounds are among the most potent nicotinic antagonists known. We have also shown that the potency of these compounds can be improved through simple modifications.