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

Saleh N, Hucke O, Kramer G, Schmidt E, Montel F, Lipinski R, Ferger B, Clark T, Hildebrand PW, Tautermann CS (2018)

Publication Status: Published

Publication Type: Journal article

Publication year: 2018

Journal

Angewandte Chemie International Edition Wiley

Publisher: WILEY-V C H VERLAG GMBH

Book Volume: 57

Pages Range: 2580-2585

Journal Issue: 10

DOI: 10.1002/anie.201708764

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.

Authors with CRIS profile

Timothy Clark Computer-Chemie-Centrum

Involved external institutions

Boehringer Ingelheim Pharma GmbH & Co. KG DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE)

How to cite

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.

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