Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458.
Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458
Proc Natl Acad Sci U S A. 2021 Nov 30;118(48). doi: 10.1073/pnas.2102178118.
The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity, and biased agonism. The presentation of ligand bias reflects selectivity between active states of the receptor, which may result in the display of preferential engagement with one signaling pathway over another. In this study, we provide evidence that the G protein-biased mu opioid receptor (MOR) agonists SR-17018 and SR-14968 stabilize the MOR in a wash-resistant yet antagonist-reversible G protein-signaling state. Furthermore, we demonstrate that these structurally related biased agonists are noncompetitive for radiolabeled MOR antagonist binding, and while they stimulate G protein signaling in mouse brains, partial agonists of this class do not compete with full agonist activation. Importantly, opioid antagonists can readily reverse their effects in vivo. Given that chronic treatment with SR-17018 does not lead to tolerance in several mouse pain models, this feature may be desirable for the development of long-lasting opioid analgesics that remain sensitive to antagonist reversal of respiratory suppression.
配体优先促进 GPCR 激活后另一条信号通路参与的能力被称为信号偏向、功能选择性和偏向激动作用。配体偏向的表现反映了受体活性状态之间的选择性，这可能导致与另一条信号通路的优先参与。在这项研究中，我们提供了证据表明，G 蛋白偏向的μ阿片受体（MOR）激动剂 SR-17018 和 SR-14968 稳定了 MOR，使其在可抵抗洗涤但可逆转拮抗剂的 G 蛋白信号状态下。此外，我们证明这些结构相关的偏向激动剂对放射性标记的 MOR 拮抗剂结合是非竞争性的，虽然它们在小鼠脑中刺激 G 蛋白信号，但该类部分激动剂不会与完全激动剂激活竞争。重要的是，阿片类拮抗剂在体内可以很容易地逆转它们的作用。鉴于 SR-17018 慢性治疗不会导致几种小鼠疼痛模型产生耐受，因此对于开发对呼吸抑制的拮抗剂逆转仍然敏感的长效阿片类镇痛药，这一特性可能是可取的。
