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

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autor(en): Saleh N, Hucke O, Kramer G, Schmidt E, Montel F, Lipinski R, Ferger B, Clark T, Hildebrand PW, Tautermann CS
Zeitschrift: Angewandte Chemie-International Edition
Verlag: WILEY-V C H VERLAG GMBH
Jahr der Veröffentlichung: 2018
Band: 57
Heftnummer: 10
Seitenbereich: 2580-2585
ISSN: 1433-7851


Abstract

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.


FAU-Autoren / FAU-Herausgeber

Clark, Timothy apl. Prof. Dr.
Computer-Chemie-Centrum


Autor(en) der externen Einrichtung(en)
Boehringer Ingelheim Pharma GmbH & Co. KG
Charité - Universitätsmedizin Berlin


Zitierweisen

APA:
Saleh, N., Hucke, O., Kramer, G., Schmidt, E., Montel, F., Lipinski, R.,... Tautermann, C.S. (2018). Multiple Binding Sites Contribute to the Mechanism of Mixed Agonistic and Positive Allosteric Modulators of the Cannabinoid CB1 Receptor. Angewandte Chemie-International Edition, 57(10), 2580-2585. https://dx.doi.org/10.1002/anie.201708764

MLA:
Saleh, Noureldin, et al. "Multiple Binding Sites Contribute to the Mechanism of Mixed Agonistic and Positive Allosteric Modulators of the Cannabinoid CB1 Receptor." Angewandte Chemie-International Edition 57.10 (2018): 2580-2585.

BibTeX: 

Zuletzt aktualisiert 2019-06-01 um 22:10