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，实际上是大部分尼古丁 药理学，仅限于使用一小部分标准药物 (例如，尼古丁等尼古丁类物质、尼古丁代谢物 可替宁，非竞争性尼古丁拮抗剂，如甲氨基甲胺， 尼古丁神经毒素，如银环蛇毒素)，和/或(至少对 结构-活性研究)主要集中在使用 外周尼古丁受体制剂。尽管这样的研究是 显然是必要的，通过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， 尤其是在中枢神经系统的层面上。此信息 在结构的表述方面尤其受到限制- 活动关系和药物开发/药物设计。某物 作为尼古丁受体药效团的基础 尼古丁尚未被开发出来。很明显，在不太 很久以前就没有尼古丁制剂了，也没有共同的 和可靠的方法，由此这些代理的中心活动可以 检查过了。随着绑定方法的出现和 适当的放射性配基，我们现在可以解决一些重要的问题；然而， 对新的尼古丁制剂的需求依然存在。我们已经发起了 通过合成所需化合物进行的研究 基础工作；我们现在希望进一步扩展这些研究并应用 这项工作的成果。我们建议进行一系列研究，以 确定和开发中枢尼古丁受体药效团，并 挑战/确认我们实验室已经提出的约束性假设。 具体来说，我们将：(A)合成特定的尼古丁部分结构 以及在首次构效关系基础上设计的相关化合物 对烟碱剂进行的调查，(B)合成 构象受限的尼古丁和相关试剂的测试距离 假设，(C)进行分子模拟研究，并利用其他 用于帮助开发和改进 中枢尼古丁受体药效团，(D)利用放射性配基结合 将数据作为开发/改进药效团的主要输入来源 (E)获得药物识别(尼古丁训练的大鼠)， 抗伤害感受剂(小鼠)和运动(小鼠)关于目标化合物的数据 一种功能活动的量度。这项工作的长期目标是 确定不同的尼古丁受体亚单位是否会表现出不同的 药效团的要求，并利用这些信息开发亚型- 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.