Weiss B, Zhang S P, Zhou L W
Department of Pharmacology, Medical College of Pennsylvania & Hahnemann University, Philadelphia 19129, USA.
Life Sci. 1997;60(7):433-55. doi: 10.1016/s0024-3205(96)00566-8.
Recent advances in molecular biology have provided pharmacologists the opportunity of developing an entirely new type of agent for studying and treating a variety of biological disorders. These agents, termed antisense oligodeoxynucleotides, have as their target the messenger RNAs encoding specific proteins. They act by binding to selected portions of these mRNAs through complimentary interactions and thereby prevent the synthesis of these proteins. These novel pharmacological tools have the promise of being easier to design and being more selective and predictable in their actions. In addition, insofar as agents targeted to receptors for neurotransmitters are concerned, unlike the classical pharmacological agents, these new compounds may not lead to the upregulation of the very receptors the drugs are designed to inhibit. The present review summarizes briefly studies on the effect of oligodeoxynucleotides antisense to the mRNAs encoding the various subtypes of the dopamine receptor. The studies show that oligodeoxynucleotides antisense to the D2 dopamine receptor when intracerebroventricularly into brains of rodents are rapidly taken up into the brain tissue, distributed to brain cells, and produce effects characteristic of highly selective D2 dopamine antagonists. The compounds also produced specific reductions in the levels of D2 dopamine receptor mRNA and D2 dopamine receptors. Similarly, injecting an antisense oligodeoxynucleotide targeted to the D1 dopamine receptor mRNA produces effects characteristic of D1 dopamine receptor antagonists. Other studies using these agents has produced evidence that there is a small pool of receptors that turn over very rapidly and which constitute the functional pool of these receptors. The evidence suggests further that antisense oligodeoxynucleotides inhibit the synthesis of this small functional pool of dopamine receptors, thereby providing an explanation of why there is often a discordance between changes in dopaminergic function and changes in the levels of dopamine receptors. Studies of antisense oligodeoxynucleotides targeted to the other subtypes of dopamine receptor may help reveal the biological roles that these and other newly discovered subtypes of neurotransmitter receptors have. They may also provide an entirely new and potentially more selective therapeutic regimen for altering the functions of these receptors.
分子生物学的最新进展为药理学家提供了开发一种全新类型药物的机会，用于研究和治疗各种生物紊乱。这些药物被称为反义寡脱氧核苷酸，其作用靶点是编码特定蛋白质的信使核糖核酸。它们通过互补相互作用与这些信使核糖核酸的选定部分结合，从而阻止这些蛋白质的合成。这些新型药理工具有望更易于设计，并且在作用上更具选择性和可预测性。此外，就针对神经递质受体的药物而言，与传统药理药物不同，这些新化合物可能不会导致药物旨在抑制的受体上调。本综述简要总结了针对编码多巴胺受体各种亚型的信使核糖核酸的反义寡脱氧核苷酸作用的研究。研究表明，将针对D2多巴胺受体的反义寡脱氧核苷酸脑室内注射到啮齿动物脑中时，它们会迅速被脑组织摄取，分布到脑细胞中，并产生高度选择性D2多巴胺拮抗剂的特征性作用。这些化合物还使D2多巴胺受体信使核糖核酸和D2多巴胺受体的水平特异性降低。同样，注射针对D1多巴胺受体信使核糖核酸的反义寡脱氧核苷酸会产生D1多巴胺受体拮抗剂的特征性作用。使用这些药物的其他研究已产生证据表明，存在一小部分更新换代非常迅速的受体，它们构成了这些受体的功能库。证据还进一步表明，反义寡脱氧核苷酸抑制了这一小部分功能性多巴胺受体的合成，从而解释了为什么多巴胺能功能的变化与多巴胺受体水平的变化之间常常存在不一致。针对多巴胺受体其他亚型的反义寡脱氧核苷酸研究可能有助于揭示这些以及其他新发现的神经递质受体亚型所具有的生物学作用。它们还可能为改变这些受体的功能提供一种全新的、可能更具选择性的治疗方案。
