Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
Molecules. 2021 Sep 18;26(18):5677. doi: 10.3390/molecules26185677.
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--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.
充分的疼痛管理，特别是慢性疼痛，仍然是现代医学面临的主要挑战。由于与阿片类药物长期使用相关的严重副作用，目前的药物治疗提供的长期解决方案并不令人满意。吗啡和结构相关的衍生物（例如，羟考酮、羟吗啡酮、丁丙诺啡）是高效的阿片类镇痛药，通过激活阿片受体发挥作用，其中μ-阿片受体亚型是主要的分子靶点。然而，它们也会导致成瘾和过量死亡，这导致了过去几十年全球阿片类药物危机。因此，需要研究努力来克服现有疼痛疗法的局限性，旨在提高治疗效果并减少并发症。本综述介绍了 14-氧代-甲基吗啡-6-酮的最新化学和药理学进展，以寻找更安全的疼痛治疗药物。我们专注于药物设计策略和结构-活性关系，研究吗啡骨架上位置 5、6、14 和 17 的特定修饰，旨在帮助发现具有更好药理特性、更强镇痛作用和更少不良作用的阿片类镇痛药。吗啡骨架上的靶向分子修饰可以提供新型阿片类药物作为针对多种阿片受体的双功能或多功能配体，作为对μ-阿片受体选择性镇痛药的有吸引力的替代品。
