Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139, Firenze, Italy.
Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.
Eur J Pharmacol. 2020 Sep 15;883:173183. doi: 10.1016/j.ejphar.2020.173183. Epub 2020 Jun 10.
Although agonists and antagonists of muscarinic receptors have been known for long time, there is renewed interest in compounds (such as allosteric or bitopic ligands, or biased agonists) able to differently and selectively modulate these receptors. As a continuation of our previous research, we designed a new series of dimers of the well-known cholinergic agonist carbachol. The new compounds were tested on the five cloned human muscarinic receptors (hM) expressed in CHO cells by means of equilibrium binding experiments, showing a dependence of the binding affinity on the length and position of the linker connecting the two monomers. Kinetic binding studies revealed that some of the tested compounds were able to slow the rate of NMS dissociation, suggesting allosteric behavior, also supported by docking simulations. Assessment of ERK1/2 phosphorylation on hM, hM and hM activation showed that the new compounds are endowed with muscarinic antagonist properties. At hM receptors, some compounds were able to stimulate GTPγS binding but not cAMP accumulation, suggesting a biased behavior. Classification, Molecular and cellular pharmacology.
虽然激动剂和拮抗剂的毒蕈碱型乙酰胆碱受体已经有很长一段时间,有重新产生兴趣的化合物(如变构或双靶点配体,或偏向激动剂)能够不同和选择性调节这些受体。作为我们之前的研究的延续,我们设计了一系列新的二聚体的著名的胆碱能激动剂卡巴胆碱。新的化合物在平衡结合实验中测试了五个克隆的人毒蕈碱型乙酰胆碱受体(hM)表达在 CHO 细胞,显示结合亲和力的依赖性的长度和位置的连接器连接两个单体。动力学结合研究表明,一些测试的化合物能够减缓 NMS 解离的速度,表明变构行为,也支持对接模拟。评估 hM, hM 和 hM 磷酸化 ERK1/2 的受体显示,新的化合物具有毒蕈碱拮抗剂的特性。在 hM 受体,一些化合物能够刺激 GTPγS 结合但不 cAMP 积累,表明偏向行为。分类、分子和细胞药理学。
