Van Gelderen J G, Daeffler L, Scherrer D, Mousli M, Landry Y, Gies J P
Laboratoire de Neuroimmunopharmacologie, INSERM U-425, Université Louis Pasteur-Strasbourg I, Illkirch, France.
J Recept Signal Transduct Res. 1996 Jan-Mar;16(1-2):135-48. doi: 10.3109/10799899609039945.
In this study we looked for evidence regarding a correlation between M2-muscarinic receptor binding affinity and ligand intrinsic activity. Guanine nucleotide-binding protein-coupled receptors have been shown to exist in both a high affinity and a low affinity, agonist state. The agonist [3H]Oxotremorine-M, was used to determine the affinity of compounds for the high affinity state and the antagonist, [3H]N-methylscopolamine, plus GppNHp, was used to determine the affinity for the low agonist state. The magnitude of the difference in the affinity a compound has for the high versus the low agonist state of the receptor has been related to the intrinsic activity of the compound. NMS/Oxo-M ratios were established for muscarinic agonists, partial agonists and antagonists. NMS/Oxo-M ratios varied from 1695 for the agonist carbachol to 1.9 for the antagonist AFDX-166 with intermediate values for the partial agonists oxotremorine-M, pilocarpine and RS86 (233, 36 and 17 respectively). Intrinsic activity was assessed by receptor-mediated Gi-protein GTPase activity. Indeed, a close correlation (r=0.92) was found between the NMS/Oxo-M ratios of the ligands on the one hand, and their ability to activate the M2-receptor coupled Gi-protein on the other.
在本研究中，我们探寻了有关M2毒蕈碱受体结合亲和力与配体内在活性之间相关性的证据。已表明鸟嘌呤核苷酸结合蛋白偶联受体以高亲和力和低亲和力激动剂状态存在。激动剂[3H]氧代震颤素-M用于测定化合物对高亲和力状态的亲和力，拮抗剂[3H]N-甲基东莨菪碱加GppNHp用于测定对低激动剂状态的亲和力。化合物对受体高激动剂状态与低激动剂状态的亲和力差异大小与该化合物的内在活性有关。为毒蕈碱激动剂、部分激动剂和拮抗剂建立了NMS/Oxo-M比率。NMS/Oxo-M比率范围从激动剂卡巴胆碱的1695到拮抗剂AFDX-166的1.9，部分激动剂氧代震颤素-M、毛果芸香碱和RS86的比率介于中间（分别为233、36和17）。通过受体介导的Gi蛋白GTP酶活性评估内在活性。事实上，一方面配体的NMS/Oxo-M比率与另一方面它们激活M2受体偶联Gi蛋白的能力之间发现了密切相关性（r = 0.92）。
