Kem W R
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville 32610-0267, USA.
Invert Neurosci. 1997 Sep-Dec;3(2-3):251-9. doi: 10.1007/BF02480382.
Naturally occurring toxins can often serve as useful chemical tools for investigating signalling processes in nervous and other systems. Tetrodotoxin and alpha-bungarotoxin are prime examples of toxins which are widely used in neurobiological research. Some toxins may also become molecular models for designing new drugs. Usually drugs are small, non-peptide molecules, as these display better bioavailability, longer durations of action and are less likely to generate immune responses. The relatively large size and conformational flexibility of peptides and protein toxins makes them more challenging molecular models for rational drug design. This article considers a marine invertebrate toxin, anabaseine, and describes how manipulation of the structure of this alkaloid has provided a drug candidate which selectively stimulates mammalian brain alpha7 nicotinic receptors. Numerous anabaseine analogs were synthesized and subjected to a variety of pharmacological, behavioral and toxcicological tests. This led to the choice of GTS-21 (also known as 3-(2,4-dimethoxybenzylidene)-anabaseine or DMXBA), as a drug candidate for the treatment of Alzheimer's dementia. The chemical and pharmacological properties of GTS-21 are compared with those of the initial lead compound, anabaseine.
天然存在的毒素常常可作为研究神经及其他系统信号传导过程的有用化学工具。河豚毒素和α-银环蛇毒素是在神经生物学研究中广泛使用的毒素的典型例子。一些毒素还可能成为设计新药的分子模型。通常药物是小分子、非肽类分子，因为这些分子具有更好的生物利用度、更长的作用持续时间，并且产生免疫反应的可能性较小。肽类和蛋白质毒素相对较大的尺寸和构象灵活性使其成为合理药物设计中更具挑战性的分子模型。本文探讨了一种海洋无脊椎动物毒素——无碱基，并描述了对这种生物碱结构的操控如何产生了一种选择性刺激哺乳动物脑α7烟碱受体的候选药物。合成了众多无碱基类似物，并对其进行了各种药理学、行为学和毒理学测试。这使得GTS-21（也称为3-(2,4-二甲氧基亚苄基)-无碱基或DMXBA）被选为治疗阿尔茨海默病痴呆症的候选药物。将GTS-21的化学和药理学特性与初始先导化合物无碱基的特性进行了比较。
