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Angew Chem Int Ed Engl. 2018 Mar 1;57(10):2580-2585. doi: 10.1002/anie.201708764. Epub 2018 Feb 2.

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

Author information

1
Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Institute of Medical Physics and Biophysics, Charitéplatz 1, 10117, Berlin, Germany.
2
Department for Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Straße 65, 88397, Biberach an der Riss, Germany.
3
Department for CNS research, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Straße 65, 88397, Biberach an der Riss, Germany.
4
Department for Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Straße 65, 88397, Biberach an der Riss, Germany.
5
Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstraße 25, 91052, Erlangen, Germany.
6
Universität Leipzig, Institute of Medical Physics and Biophysics, Härtelstraße 16-18, 04107, Leipzig, Germany.

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 CP 55,940 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.

KEYWORDS:

G-protein-coupled receptors; allostery; cannabinoid receptors; metadynamics

PMID:
29314474
DOI:
10.1002/anie.201708764
[Indexed for MEDLINE]

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