Chojnacka-Wójcik E, Kłodzinska A, Pilc A
Institute of Pharmacology, Polish Academy of Sciences, Krakow, Smetna.
Curr Opin Investig Drugs. 2001 Aug;2(8):1112-9.
The glutamatergic system has received considerable attention over recent years as a potential target for anxiolytic drugs. In spite of the pronounced anxiolytic-like effects of competitive and non-competitive antagonists of NMDA receptors in animal models of anxiety, these substances can not be regarded as potential anxiolytic drugs, mainly due to their side-effect profiles (eg, ataxia, myorelaxation, impairment of learning and memory processes and psychotomimetic effects). Antagonists and partial agonists of the glycine, receptor inhibit function of the NMDA receptor complex and evoke in animals an anxiolytic-like response. Although data concerning anti-anxiety-like effects of glycine, receptor antagonists are not very promising, studies are underway to develop new, brain-penetrating agents devoid of side effects. Further developments are necessary to more fully elucidate the possible involvement of AMPA/kainate receptors in anxiety. The recent discovery of metabotropic glutamate receptors, which modulate the function of the glutamatergic system, offers new hope for discovery of a new generation of anxiolytics. MPEP, a highly selective, brain penetrable, noncompetitive mGlu5 receptor antagonist, evokes anxiolytic-like effects in several animal models of anxiety, remaining remarkably free of side effects. LY-354740, a selective brain-penetrable group II mGlu receptor agonist, evokes marked anxiolytic-like effects in animal models of anxiety. LY-354740 causes mild sedation in mice, does not disturb motor coordination and has no potential to cause dependence. Therefore mGlu receptor ligands may become the anxiolytics of the future, free from the side effects characteristic of benzodiazepines.
近年来，谷氨酸能系统作为抗焦虑药物的潜在靶点受到了广泛关注。尽管NMDA受体的竞争性和非竞争性拮抗剂在动物焦虑模型中具有显著的抗焦虑样作用，但这些物质不能被视为潜在的抗焦虑药物，主要是由于它们的副作用（如共济失调、肌松弛、学习和记忆过程受损以及拟精神病效应）。甘氨酸受体的拮抗剂和部分激动剂抑制NMDA受体复合物的功能，并在动物中引发抗焦虑样反应。尽管关于甘氨酸受体拮抗剂抗焦虑样作用的数据不太乐观，但正在进行研究以开发新的、无副作用的脑渗透性药物。需要进一步开展研究，以更全面地阐明AMPA/海人藻酸受体在焦虑中可能的作用。代谢型谷氨酸受体的发现可调节谷氨酸能系统的功能，为新一代抗焦虑药物的研发带来了新希望。MPEP是一种高度选择性、可穿透脑的非竞争性mGlu5受体拮抗剂，在多种动物焦虑模型中具有抗焦虑样作用，且几乎没有副作用。LY-354740是一种选择性可穿透脑的II组mGlu受体激动剂，在动物焦虑模型中具有显著的抗焦虑样作用。LY-354740在小鼠中引起轻度镇静，不影响运动协调，也没有成瘾的可能性。因此，mGlu受体配体可能成为未来的抗焦虑药物，没有苯二氮䓬类药物特有的副作用。
