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. 2023 May 9;14:2672. doi: 10.1038/s41467-023-37864-4

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — a AMG315 stabilizes the ‘toggle switch’ residues W356^6.48 and F200^3.36 in the active state. b Ligand interaction with residues W356^6.48 and F200^3.36. The methyl group in AMG315 (circled black) not present in anandamide interacts with the ‘toggle switch’. c In the simulation, anandamide stabilizes active-like conformations of W356^6.48 significantly less when compared individually to FUB (MDMB-Fubinaca) (p = 0.02, two-sided Welch’s t-test) and to AMG315 (p = 0.04), as well as when compared to both FUB (MDMB-Fubinaca) and AMG315 as a group (p = 0.003). Data are presented as mean values ± SEM from n = 6 independent simulations (**p < 0.01). d Molecular docking shows that the R-stereochemistry (AMG317) instead of the S-stereochemistry at position 13 (AMG315), repositions the methyl group away from the “toggle switch”. Insert below: chemical structures of 13-methyl substituted anandamide analogs, AMG313 (13S-enantiomer) and AM8141 (13R-enantiomer). e The methyl group at position 1’ (circled red in 3B) on AMG315 interacts with residues on ECL2 (Ile267^ECL2) and the extracellular region of TM7 (K376^7.32). This substitution is not found in anandamide.