Institut de Pharmacologie de Sherbrooke, Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12e avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, Brussels 1050, Belgium.
Pharmacol Res. 2024 Nov;209:107408. doi: 10.1016/j.phrs.2024.107408. Epub 2024 Sep 21.
Chronic pain, which affects more than one-third of the world's population, represents one of the greatest medical challenges of the 21st century, yet its effective management remains sub-optimal. The 'gold standard' for the treatment of moderate to severe pain consists of opioid ligands, such as morphine and fentanyl, that target the µ-opioid receptor (MOP). Paradoxically, these opioids also cause serious side effects, including constipation, respiratory depression, tolerance, and addiction. In addition, the development of opioid-use disorders, such as opioid diversion, misuse, and abuse, has led to the current opioid crisis, with dramatic increases in addiction, overdoses, and ultimately deaths. As pain is a complex, multidimensional experience involving a variety of pathways and mediators, dual or multitarget ligands that can bind to more than one receptor and exert complementary analgesic effects, represent a promising avenue for pain relief. Indeed, unlike monomodal therapeutic approaches, the modulation of several endogenous nociceptive systems can often result in an additive or even synergistic effect, thereby improving the analgesic-to-side-effect ratio. Here, we provide a comprehensive overview of research efforts towards the development of dual- or multi-targeting opioid/nonopioid hybrid ligands for effective and safer pain management. We reflect on the underpinning discovery rationale by discussing the design, medicinal chemistry, and in vivo pharmacological effects of multitarget antinociceptive compounds.
慢性疼痛影响了全球超过三分之一的人口，是 21 世纪最大的医学挑战之一，但有效的疼痛管理仍然不尽人意。中重度疼痛的“金标准”治疗方法包括阿片类配体，如吗啡和芬太尼，它们靶向μ-阿片受体（MOP）。矛盾的是，这些阿片类药物也会引起严重的副作用，包括便秘、呼吸抑制、耐受和成瘾。此外，阿片类药物使用障碍的发展，如阿片类药物的转移、滥用和滥用，导致了目前的阿片类药物危机，成瘾、过量用药和最终死亡的人数急剧增加。由于疼痛是一种复杂的、多维的体验，涉及多种途径和介质，因此能够与多个受体结合并发挥互补镇痛作用的双或多靶标配体，代表了一种有前途的缓解疼痛的途径。事实上，与单模态治疗方法不同，几种内源性伤害感受系统的调节通常会产生相加甚至协同的效果，从而提高镇痛效果与副作用的比值。在这里，我们全面概述了开发双重或多靶向阿片类/非阿片类混合配体以进行有效和更安全的疼痛管理的研究工作。我们通过讨论多靶抗伤害化合物的设计、药物化学和体内药理学作用，反思了其潜在的发现原理。
