Department of Pharmaceutical and Administrative Sciences, Concordia University Wisconsin School of Pharmacy, 12800 N. Lake Shore Drive, Mequon, WI 53092, USA.
Department of Pharmaceutical and Administrative Sciences, Concordia University Wisconsin School of Pharmacy, 12800 N. Lake Shore Drive, Mequon, WI 53092, USA; CUW Center for Structure-Based Drug Discovery and Development, Concordia University Wisconsin School of Pharmacy, 12800 N. Lake Shore Drive, Mequon, WI 53092, USA.
Pharmacol Res. 2023 Nov;197:106966. doi: 10.1016/j.phrs.2023.106966. Epub 2023 Oct 20.
Though efficacious in managing chronic, severe pain, opioid analgesics are accompanied by significant adverse effects including constipation, tolerance, dependence, and respiratory depression. The life-threatening risks associated with µ opioid receptor agonist-based analgesics challenges their use in clinic. A rational approach to combatting these adverse effects is to develop agents that incorporate activity at a second pharmacologic target in addition to µ opioid receptor activation. The promise of such bivalent or bifunctional ligands is the development of an analgesic with an improved side effect profile. In this review, we highlight ongoing efforts in the development of bivalent and bifunctional analgesics that combine µ agonism with efficacy at κ and δ opioid receptors, the nociceptin opioid peptide (NOP) receptor, σ receptors, and cannabinoid receptors. Several examples of bifunctional analgesics in preclinical and clinical development are highlighted, as are strategies being employed toward the rational design of novel agents.
尽管阿片类镇痛药在治疗慢性、严重疼痛方面有效，但它们也伴随着显著的不良反应，包括便秘、耐受性、依赖性和呼吸抑制。与μ阿片受体激动剂类镇痛药相关的危及生命的风险挑战了它们在临床上的应用。对抗这些不良反应的合理方法是开发除了激活μ阿片受体以外还能作用于第二个药理学靶点的药物。这种双价或双功能配体的前景是开发出一种具有改善的副作用谱的镇痛药。在这篇综述中，我们强调了正在进行的开发双价和双功能镇痛药的努力，这些药物将μ激动作用与κ和δ阿片受体、孤啡肽阿片肽（NOP）受体、σ受体和大麻素受体的疗效结合在一起。强调了一些处于临床前和临床开发阶段的双功能镇痛药的例子，以及正在采用的合理设计新型药物的策略。
