DeHaven-Hudkins D L, Dolle R E
Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA.
Curr Pharm Des. 2004;10(7):743-57. doi: 10.2174/1381612043453036.
Mediation of antinociception via opioid receptors located in the periphery is a viable strategy to produce analgesia without the occurrence of side effects associated with stimulation of opioid receptors located in the central nervous system. Peripheral opioid receptors are particularly important in inflammatory pain states and in the responses to pruritogenic stimuli, and have been implicated in the transmission of visceral pain. Medicinal chemistry approaches to achieve peripheralization of opioid agonists have started with a centrally acting opioid agonist as a template, and introduced features of lipophilicity, hydrophilicity, or combined lipophilicity and hydrophilicity to achieve amphiphilicity. Quaternarization of centrally acting opioid agonists or identification of compounds that serve as substrates for the mdr transporter to achieve transport out of the brain has also been employed. The in vivo assays used to identify peripherally selective compounds have measured a variety of behavioral and pharmacokinetic endpoints, with varying degrees of predictability. This review focuses on a discussion of these methods, as well as a review of those compounds where sufficient data exist to support a claim of peripheralization in vivo.
通过位于外周的阿片受体介导抗伤害感受是一种可行的策略，可产生镇痛作用而不会出现与刺激位于中枢神经系统的阿片受体相关的副作用。外周阿片受体在炎症性疼痛状态以及对致痒刺激的反应中尤为重要，并且与内脏痛的传递有关。实现阿片类激动剂外周化的药物化学方法始于以中枢作用的阿片类激动剂为模板，并引入亲脂性、亲水性或亲脂性与亲水性结合的特征以实现两亲性。也采用了对中枢作用的阿片类激动剂进行季铵化或鉴定用作mdr转运蛋白底物以实现从脑内转运出去的化合物的方法。用于鉴定外周选择性化合物的体内试验测量了各种行为和药代动力学终点，其可预测性程度各不相同。本综述重点讨论这些方法，以及对那些有足够数据支持体内外周化主张的化合物的综述。
