Kleczkowska Patrycja, Lipkowski Andrzej W, Tourwé Dirk, Ballet Steven
Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
Curr Pharm Des. 2013;19(42):7435-50. doi: 10.2174/138161281942140105165646.
To address the different types of pain (e.g. acute, chronic, neuropathic) different classes of medications, mainly non-steroidal anti-inflammatory drugs and narcotics (opioids), are used. More specifically, the alleviation or treatment of moderate to severe pain states commonly invokes the use of opioids. Unfortunately, their chronic administration induces various undesirable side effects, such as for example physical dependence and tolerance. One strategy to overcome these major side effects and to prolong the antinociceptive efficiency of the applied drugs involves the creation of multifunctional compounds which contain hybridized structures. Combination of opioid agonist and antagonist pharmacophores in a single chemical entity has been considered and extensively investigated, but opioids have also been combined with other bioactive neurotransmitters and peptide hormones that are involved in pain perception (e.g. substance P, neurotensin, cholecystokinin, cannabinoids, melanocortin ligands, etc.). Such novel chimeras (also called designed multiple ligands or twin/triplet drugs), may interact independently with their respective receptors and potentially result in more effective antinociceptive properties. The designed multiple ligands presented in this work include opioid-non-opioid peptide dimer analogs, mixed peptidic- non-peptidic bifunctional ligands and dual non-peptidic dimers. The main focus herein is placed on the design and biological evaluation of these multiple opioid compounds, rather than the synthetic approach and preparation.
为了应对不同类型的疼痛（如急性、慢性、神经性疼痛），人们使用了不同种类的药物，主要是非甾体抗炎药和麻醉剂（阿片类药物）。更具体地说，缓解或治疗中度至重度疼痛状态通常需要使用阿片类药物。不幸的是，长期使用这些药物会引发各种不良副作用，例如身体依赖性和耐受性。克服这些主要副作用并延长所用药物的镇痛效果的一种策略是合成包含杂交结构的多功能化合物。人们已经考虑并广泛研究了将阿片类激动剂和拮抗剂药效基团结合在单一化学实体中的方法，但阿片类药物也与其他参与疼痛感知的生物活性神经递质和肽类激素（如P物质、神经降压素、胆囊收缩素、大麻素、黑皮质素配体等）进行了组合。这种新型嵌合体（也称为设计型多配体或双/三联药物）可能会与其各自的受体独立相互作用，并可能产生更有效的镇痛特性。本文介绍的设计型多配体包括阿片类-非阿片类肽二聚体类似物、混合肽类-非肽类双功能配体和双非肽二聚体。本文的主要重点是这些多种阿片类化合物的设计和生物学评估，而非合成方法和制备过程。
