Endomorphin derivatives with improved pharmacological properties.
Endomorphin derivatives with improved pharmacological properties.
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DOI：
10.2174/0929867311320220002
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发表时间：
2013-06
影响因子：
4.1
通讯作者：
P. Varamini;J. Blanchfield;I. Toth
中科院分区：
文献类型：
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作者：
P. Varamini;J. Blanchfield;I. Toth
中枢作用的阿片类药物，如吗啡，是治疗剧烈疼痛最常用的止痛药。然而，由于产生了一系列不良反应，如便秘、呼吸抑制、耐受性和身体依赖，它们的有效性受到限制。此外，阿片类药物对神经病理性疼痛的疗效一般较差。内吗啡肽-1和-2是两种内源性阿片肽，已被证明在急性和神经病理性疼痛的啮齿动物模型中产生强大的抗伤害作用，且副作用比阿片类生物碱少。然而，未经修饰的天然内吗啡素不太适合临床应用。像所有的小肽一样，内吗啡素的代谢稳定性差，相对不能穿透胃肠粘膜和血脑屏障。自从1997年内吗啡类药物被发现以来，人们已经设计和合成了大量的内吗啡类似物，目的是开发具有更好的屏障穿透性和抗酶降解能力的化合物。在这篇综述中，我们描述了到目前为止已经采取的各种策略，以克服与内吗啡相关的主要缺点。除了应用肽酶抑制剂外，它们还包括化学修饰以生产局部或全球限制的多肽类似物，与前一种策略相比，这是次要的。还讨论了设计和合成具有药理活性、不良反应较少的内吗啡类似物的各种方法，从而深入了解副作用改善的阿片肽的开发。
Centrally acting opioids, such as morphine, are the most frequently used analgesic agents for the treatment of severe pain. However, their usefulness is limited by the production of a range of adverse effects such as constipation, respiratory depression, tolerance and physical dependence. In addition, opioids generally exhibit poor efficacy against neuropathic pain. Endomorphin-1 and -2, two endogenous opioid peptides, have been shown to produce potent antinociception in rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, native endomorphins are poorly suited to clinical applications without modifications. Like all small peptides, endomorphins suffer from poor metabolic stability and a relative inability to penetrate the gastro-intestinal mucosa and blood-brain-barrier. Since the discovery of endomorphins in 1997, a huge number of endomorphin analogs have been designed and synthesized with the aim of developing compounds with improved barrier penetration and resistance to enzymatic degradation. In this review we describe various strategies that have been adopted so far to conquer the major drawbacks associated with endomorphins. They include chemical modifications to produce locally or globally-restricted peptide analogs in addition to application of peptidase inhibitors, which is of minor importance compared to the former strategy. Diverse approaches that resulted in the design and synthesis of pharmacologically active endomorphin analogs with less adverse effects are also discussed giving an insight into the development of opioid peptides with an improved side effect profile.