Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany.
Br J Pharmacol. 2018 Jul;175(14):2857-2868. doi: 10.1111/bph.13809. Epub 2017 May 26.
Classical opioid analgesics, including morphine, mediate all of their desired and undesired effects by specific activation of the μ-opioid receptor (μ receptor). The use of morphine for treating chronic pain, however, is limited by the development of constipation, respiratory depression, tolerance and dependence. Analgesic effects can also be mediated through other members of the opioid receptor family such as the κ-opioid receptor (κ receptor), δ-opioid receptor (δ receptor) and the nociceptin/orphanin FQ peptide receptor (NOP receptor). Currently, a new generation of opioid analgesics is being developed that can simultaneously bind with high affinity to multiple opioid receptors. With this new action profile, it is hoped that additional analgesic effects and fewer side effects can be achieved. Recent research is mainly focused on the development of bifunctional μ/NOP receptor agonists, which has already led to novel lead structures such as the spiroindole-based cebranopadol and a compound class with a piperidin-4-yl-1,3-dihydroindol-2-one backbone (SR16835/AT-202 and SR14150/AT-200). In addition, the ornivol BU08028 is an analogue of the clinically well-established buprenorphine. Moreover, the morphinan-based nalfurafine exerts its effect with a dominant κ receptor-component and is therefore utilized in the treatment of pruritus. The very potent dihydroetorphine is a true multi-receptor opioid ligand in that it binds to μ, κ and δ receptors. The main focus of this review is to assess the paradigm of opioid ligands targeting multiple receptors with a single chemical entity. We reflect on this rationale by discussing the biological actions of particular multi-opioid receptor ligands, but not on their medicinal chemistry and design.
This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.
经典阿片类镇痛药，包括吗啡，通过特异性激活μ-阿片受体（μ受体）来介导其所有所需和不需要的作用。然而，由于便秘、呼吸抑制、耐受和依赖的发展，吗啡用于治疗慢性疼痛受到限制。阿片类受体家族的其他成员，如κ-阿片受体（κ受体）、δ-阿片受体（δ受体）和孤啡肽/孤啡肽 FQ 肽受体（NOP 受体），也可以介导镇痛作用。目前，正在开发新一代阿片类镇痛药，这些药物可以同时与多种阿片受体高亲和力结合。通过这种新的作用模式，有望获得额外的镇痛作用和更少的副作用。最近的研究主要集中在开发双功能μ/NOP 受体激动剂上，这已经导致了新型的先导结构，如基于螺吲哚的塞布诺啡和具有哌啶-4-基-1,3-二氢吲哚-2-酮骨架的化合物类（SR16835/AT-202 和 SR14150/AT-200）。此外，ornivol BU08028 是临床应用良好的丁丙诺啡类似物。此外，吗啡烷类纳呋拉啡主要通过 κ 受体发挥作用，因此用于治疗瘙痒。非常有效的二氢埃托啡是一种真正的多受体阿片配体，它与 μ、κ 和 δ 受体结合。本文的主要重点是评估用单一化学实体靶向多种受体的阿片类配体范例。通过讨论特定多阿片受体配体的生物学作用来反映这一原理，但不讨论其药物化学和设计。
本文是阿片类药物药理学新兴领域专题的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.
