Multiple Binding Sites Contribute to the Mechanism of Mixed Agonistic and Positive Allosteric Modulators of the Cannabinoid CB1 Receptor

被引:46
|
作者
Saleh, Noureldin [1 ,2 ,3 ,4 ]
Hucke, Oliver [7 ]
Kramer, Gert [9 ]
Schmidt, Esther [8 ]
Montel, Florian [7 ]
Lipinski, Radoslaw [7 ]
Ferger, Boris [9 ]
Clark, Timothy [6 ]
Hildebrand, Peter W. [1 ,2 ,3 ,4 ,5 ]
Tautermann, Christofer S. [7 ]
机构
[1] Charite Univ Med Berlin, Charitepl 1, D-10117 Berlin, Germany
[2] Free Univ Berlin, Charitepl 1, D-10117 Berlin, Germany
[3] Humboldt Univ, Charitepl 1, D-10117 Berlin, Germany
[4] Berlin Inst Hlth, Inst Med Phys & Biophys, Charitepl 1, D-10117 Berlin, Germany
[5] Univ Leipzig, Inst Med Phys & Biophys, Hartelstr 16-18, D-04107 Leipzig, Germany
[6] Friedrich Alexander Univ Erlangen Nurnberg, Comp Chem Ctr, Nagelsbachstr 25, D-91052 Erlangen, Germany
[7] Boehringer Ingelheim Pharma GmbH & Co KG, Dept Med Chem, Birkendorfer Str 65, D-88397 Biberach, Germany
[8] Boehringer Ingelheim Pharma GmbH & Co KG, Dept Drug Discovery Sci, Birkendorfer Str 65, D-88397 Biberach, Germany
[9] Boehringer Ingelheim Pharma GmbH & Co KG, Dept CNS Res, Birkendorfer Str 65, D-88397 Biberach, Germany
关键词
allostery; cannabinoid receptors; G-protein-coupled receptors; metadynamics; ENDOCANNABINOID SYSTEM; COMPLEXES; LIGANDS; OBESITY; MEMORY; THC;
D O I
10.1002/anie.201708764
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The cannabinoid CB1 receptor (CB1R) is an abundant metabotropic G-protein-coupled receptor that has been difficult to address therapeutically because of CNS side effects exerted by orthosteric drug candidates. Recent efforts have focused on developing allosteric modulators that target CB1R. Compounds from the recently discovered class of mixed agonistic and positive allosteric modulators (Ago-PAMs) based on 2-phenylindoles have shown promising functional and binding properties as CB1R ligands. Here, we identify binding modes of both the CP55,940 agonist and GAT228, a 2-phenylindole allosteric modulator, by using our metadynamics simulation protocol, and quantify their affinity and cooperativity by atomistic simulations. We demonstrate the involvement of multiple adjunct binding sites in the Ago-PAM characteristics of the 2-phenylindole modulators and explain their ability to compete with orthosteric agonists at higher concentrations. We validate these results experimentally by showing the contribution of multiple sites on the allosteric binding of ZCZ011, another homologous member of the class, together with the orthosteric agonist.
引用
收藏
页码:2580 / 2585
页数:6
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