SYNTHESIS OF NICOTINE ANALOGS

尼古丁仍然是药物滥用研究的一个重要领域; 然而，大多数关于尼古丁受体的研究， 药理学，仅限于使用少数标准药物 (e.g.,烟碱类化合物如尼古丁、尼古丁代谢物如 可替宁，非竞争性烟碱拮抗剂如美加明， 烟碱神经毒素如银环蛇毒素），和/或（至少对于 结构-活性研究）主要集中在使用 外周尼古丁受体制剂。 虽然这些研究 显然是必要的，从使用相同的小数字获得的信息 在理解作用机制方面可能是有限的， 特别是在中枢神经系统的水平上。 这些信息 特别限制了结构的形成， 活动关系和药物开发/药物设计。 东西 作为基本的“尼古丁受体药效团”， 尼古丁还有待开发。 很明显，在不太 在很久以前，缺乏尼古丁制剂，缺乏一种常见的 和可靠的方法，从而这些代理人的中心活动， 考察 随着绑定方法的出现和 合适的放射性配体，我们现在可以解决一些重要的问题;然而， 仍然需要新的烟碱剂。 我们已经启动了 研究通过合成所需的化合物奠定必要的 我们现在希望进一步扩展这些研究，并将 这项工作的结果。 我们建议进行一系列研究， 鉴定和开发中心尼古丁受体药效团，以及 挑战/确认我们实验室已经开发的结合假设。 具体而言，我们将：（a）合成特定的尼古丁部分结构 和相关化合物的基础上设计的第一次定量构效关系 对烟碱剂进行的研究，（B）合成 构象限制的烟碱和相关试剂以测试距离 假设，（c）进行分子建模研究，并利用其他 计算的（例如，定量构效关系（QSAR）方法，以帮助开发和完善 中心烟碱受体药效团，（d）利用放射性配体结合 数据作为开发/完善药效团的主要输入来源 模型，和（e）获得药物辨别（尼古丁训练的大鼠）， 目标化合物的抗伤害感受（小鼠）和运动（小鼠）数据， 一种功能活动的衡量标准。 这项工作的长期目标是 确定不同的尼古丁受体亚基是否会表现出不同的 药效团的要求，并使用这些信息来开发亚型- 选择性烟碱配体。

Nicotine continues to be an important area of drug abuse research; however, most studies with nicotine receptors, indeed much of nicotine pharmacology, is limited to the use of a small handful of standard agents (e.g., nicotinoids such as nicotine, nicotine metabolites such as cotinine, noncompetitive nicotinic antagonists such as mecamylamine, nicotinic neurotoxins such as bungarotoxin), and/or (at least for structure-activity studies) has focussed primarily on the use of peripheral nicotine receptor preparations. Although such studies are obviously necessary, information gained from using the same small number of agents may be limiting in terms of understanding mechanisms of action, especially at the level of the central nervous system. This information is particularly restrictive with respect to formulation of structure- activity relationships and medications development/drug design. Something as basic as a 'nicotine receptor pharmacophore' for the central actions of nicotine has yet to be developed. It is fairly clear that in the not too distant past there was a lack of nicotinic agents, and lack of a common and reliable method whereby the central activity of these agents could be examined. With the advent of binding methodology and the availability of suitable radioligands, we can now address some important issues; however, a need remains for new nicotinic agents. We have already initiated studies by synthesizing compounds required to lay the necessary groundwork; we now wish to further extend these studies and to apply the results of this work. We propose to conduct a series of studies to identify and develop a central nicotine receptor pharmacophore, and to challenge/confirm binding hypotheses already developed in our laboratory. Specifically, we will: (a) synthesize specific nicotine partial-structures and related compounds designed on the basis of the first ever QSAR investigations conducted on nicotinic agents, (b) synthesize conformationally-restricted nicotinic and related agents to test distance hypotheses, (c) conduct molecular modeling studies and utilize other computational (e.g., QSAR) methods to aid in developing and refining a central nicotine receptor pharmacophore, (d) utilize radioligand binding data as a primary source of input to develop/refine the pharmacophore model, and (e) obtain drug discrimination (nicotine-trained rats), antinociceptive (mice), and locomotor (mice) data on target compounds as a measure of functional activity. The long-term goal of this work is to determine if different nicotine receptor subunits will exhibit different pharmacophore requirements and to use such information to develop subtype- selective nicotinic ligands.