Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with the mu-opioid receptor subtype as the primary molecular target. However, they also cause addiction and overdose deaths, which has led to a global opioid crisis in the last decades. Therefore, research efforts are needed to overcome the limitations of present pain therapies with the aim to improve treatment efficacy and to reduce complications. This review presents recent chemical and pharmacological advances on 14-oxygenated-N-methylmorphinan-6-ones, in the search of safer pain therapeutics. We focus on drug design strategies and structure–activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid analgesics with more favorable pharmacological properties, potent analgesia and fewer undesirable effects. Targeted molecular modifications on the morphinan scaffold can afford novel opioids as bi- or multifunctional ligands targeting multiple opioid receptors, as attractive alternatives to mu-opioid receptor selective analgesics.

中文翻译：

---

14-Oxygenated-N-methylmorphinan-6-ones 的近期化学和药理学进展

充分的疼痛管理，尤其是慢性疼痛，仍然是与现代医学相关的主要挑战。由于与长期服用镇痛药物有关的严重副作用，目前的药物疗法提供了不能令人满意的长期解决方案。吗啡和结构相关的衍生物（如羟考酮、羟吗啡酮、丁丙诺啡）是高效的阿片类镇痛药，通过激活阿片受体介导其作用，其中μ-阿片受体亚型是主要分子靶点。然而，它们也会导致成瘾和过量死亡，这导致了过去几十年的全球阿片类药物危机。因此，需要进行研究以克服目前疼痛疗法的局限性，以提高治疗效果并减少并发症。N -methylmorphinan-6-ones，在寻找更安全的疼痛疗法。我们专注于药物设计策略和对吗啡喃骨架上第 5、6、14 和 17 位特定修饰的结构-活性关系，目的是帮助发现具有更有利的药理特性、有效镇痛和更少不良反应的阿片类镇痛剂. 吗啡喃支架上的靶向分子修饰可以提供新的阿片类药物作为靶向多种阿片受体的双功能或多功能配体，作为 mu-阿片受体选择性镇痛剂的有吸引力的替代品。