Since 1952, when Gates determined the stereo structure of morphine, numerous groups have focused on discovering a nonnarcotic opioid drug. Although several natural, semisynthetic, and synthetic opioid ligands (alkaloids and peptides) have been developed in clinical studies, very few were nonnarcotic opioid drugs. One of the most important studies in the opioid field appeared in 1976, when Martin and colleagues established types of opioid receptors (these are now classified into mu, delta, and kappa types). Later, Portoghese discovered a highly selective mu type opioid receptor antagonist, beta-funaltrexamine. This led to the finding that the mu type opioid receptor was correlated to drug dependence. Consequently, delta, and particularly kappa, opioid agonists were expected to lead to ideal opioid drugs. Moreover, opioid antagonists were evaluated for the treatment of symptoms related to undesirable opioid system activation. In this chapter, we provide a short survey of opioid ligands in development and describe the discovery of the two most promising drugs, TRK-851 and TRK-820 (nalfurafine hydrochloride).

中文翻译：

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阿片类药物的临床前和临床试验。

自1952年盖茨确定吗啡的立体结构以来，许多小组就致力于发现一种非麻醉性阿片类药物。尽管在临床研究中已经开发了几种天然，半合成和合成的阿片类药物配体（生物碱和多肽），但非麻醉性阿片类药物却很少。阿片类药物领域最重要的研究之一出现在1976年，当时Martin和同事建立了阿片类药物受体的类型（现在分为mu，delta和kappa类型）。后来，Portoghese发现了一种高度选择性的mu型阿片受体拮抗剂β-富氨曲明。这导致发现mu型阿片样物质受体与药物依赖性相关。因此，预期δ，尤其是κ阿片样物质激动剂可产生理想的阿片样物质药物。此外，评价了阿片拮抗剂的治疗与不良阿片系统活化有关的症状。在本章中，我们对开发中的阿片类药物配体进行了简短调查，并描述了两种最有前途的药物TRK-851和TRK-820（盐酸纳氟拉芬）的发现。