Kivell Bronwyn M, Ewald Amy W M, Prisinzano Thomas E
School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand.
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA.
Adv Pharmacol. 2014;69:481-511. doi: 10.1016/B978-0-12-420118-7.00012-3.
Acute activation of kappa-opioid receptors produces anti-addictive effects by regulating dopamine levels in the brain. Unfortunately, classic kappa-opioid agonists have undesired side effects such as sedation, aversion, and depression, which restrict their clinical use. Salvinorin A (Sal A), a novel kappa-opioid receptor agonist extracted from the plant Salvia divinorum, has been identified as a potential therapy for drug abuse and addiction. Here, we review the preclinical effects of Sal A in comparison with traditional kappa-opioid agonists and several new analogs. Sal A retains the anti-addictive properties of traditional kappa-opioid receptor agonists with several improvements including reduced side effects. However, the rapid metabolism of Sal A makes it undesirable for clinical development. In an effort to improve the pharmacokinetics and tolerability of this compound, kappa-opioid receptor agonists based on the structure of Sal A have been synthesized. While work in this field is still in progress, several analogs with improved pharmacokinetic profiles have been shown to have anti-addictive effects. While in its infancy, it is clear that these compounds hold promise for the future development of anti-addictive therapeutics.
κ-阿片受体的急性激活通过调节大脑中的多巴胺水平产生抗成瘾作用。不幸的是，经典的κ-阿片受体激动剂具有诸如镇静、厌恶和抑郁等不良副作用，这限制了它们的临床应用。从植物鼠尾草中提取的新型κ-阿片受体激动剂Salvinorin A（Sal A）已被确定为药物滥用和成瘾的潜在治疗方法。在此，我们将Sal A与传统κ-阿片受体激动剂及几种新的类似物的临床前效应进行综述。Sal A保留了传统κ-阿片受体激动剂的抗成瘾特性，并在几个方面有所改进，包括副作用减少。然而，Sal A的快速代谢使其不利于临床开发。为了改善该化合物的药代动力学和耐受性，基于Sal A结构的κ-阿片受体激动剂已被合成。虽然该领域的工作仍在进行中，但几种药代动力学特征得到改善的类似物已显示出具有抗成瘾作用。虽然尚处于起步阶段，但很明显这些化合物在抗成瘾治疗的未来发展中具有前景。
