ANALOGUES OF METHYLLYCACONITINE

描述（由申请人提供）：我们发现了一系列新的 作为拮抗剂的生物碱甲基乌头碱（MLA）的类似物， 神经元烟碱乙酰胆碱受体（nAChR）。我们的目标 建议是确定MLA的结构方面，赋予烟碱 拮抗活性我们的假设是，MLA类似物包含更多的 MLA结构（“更像MLA”）将更有效和更有选择性 alpha 7 nAChR的拮抗剂。我们的长期目标是了解 小分子-烟碱受体结合的结构决定簇和用途 这种理解来设计和合成新的药物制剂。 我们建议根据MLA的结构制备新的类似物。这些 化合物将包括环E类似物以及结合有 环C、B、D和F。这些新的类似物应该有很好的效力， apha7 nAChR。我们建议用改进的方法制备MLA的E环类似物， 在alpha 3 nAChR的效力。我们将评估效力和受体亚型 MLA类似物的特异性。类似物活性和亚型特异性将 通过使用模型系统的结合和功能研究进行评估 同时表达CNS和外周nAChR。 总的来说，我们已经发现了一个简单的类似MLA，应该是有用的， 评估效价和nAChR亚型所需的结构要求 选择性。我们制备了四个系列的MLA类似物， 在α 7、α 3和α 4处具有效力和选择性的化合物 nAChR。这些初步研究进一步确定了结构的重要性， 在哌啶环的氮上的取代和在 琥珀酰亚胺环。我们已经开发了一种针对α 3 nAChR的结合测定法， 这对我们的工作以及烟碱配体的一般研究都是有用的 选择性 在R 03赠款的支持下，我们实现了最初的目标， 我们可以制备和评估MLA的类似物， 对手。此外，我们已经表明，这些化合物中有几种是 已知最有效的烟碱拮抗剂。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.