Structure-based discovery of cannabinoid-1 receptor agonists with reduced side effects

Tummino, T. A.; Iliopoulos-Tsoutsouvas, C.; Braz, J. M.; O'Brien, E. S.; Stein, R. M.; Craik, V.; Tran, N. K.; Ganapathy, S.; Shiimura, Y.; Tong, F.; Ho, T. C.; Radchenko, D. S.; Moroz, Y. S.; Liu, F.; Rosado, S. R.; Bhardwaj, K.; Benitez, J.; Liu, Y.; Kandasamy, H.; Normand, C.; Semache, M.; Sabbagh, L.; Glenn, I.; Irwin, J. J.; Kumar, K. K.; Makriyannis, A.; Basbaum, A. I.; Shoichet, B. K.

doi:10.1101/2023.02.27.530254

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bioRxiv · 10.1101/2023.02.27.530254

Structure-based discovery of cannabinoid-1 receptor agonists with reduced side effects

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Abstract

Large library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones for de novo synthesis and testing. Nine were active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki = 0.7 {micro}M) led to 4042, a 1.9 nM ligand and a full CB1R agonist. A cryo-EM structure of the purified enantiomer of 4042 ( 1350) in complex with CB1R-Gi1 confirmed its docked pose. The new agonist was strongly analgesic, with generally a 5-10-fold therapeutic window over sedation and catalepsy and no observable conditioned place preference. These findings suggest that new cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from their analgesia, supporting the further development of cannabinoids as pain therapeutics.

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Tummino, T. A., Iliopoulos-Tsoutsouvas, C., Braz, J. M., O'Brien, E. S., Stein, R. M., Craik, V., Tran, N. K., Ganapathy, S., Shiimura, Y., Tong, F., Ho, T. C., Radchenko, D. S., Moroz, Y. S., Liu, F., Rosado, S. R., Bhardwaj, K., Benitez, J., Liu, Y., Kandasamy, H., Normand, C., Semache, M., Sabbagh, L., Glenn, I., Irwin, J. J., Kumar, K. K., Makriyannis, A., Basbaum, A. I., Shoichet, B. K.. 2023-03-03. Structure-based discovery of cannabinoid-1 receptor agonists with reduced side effects. https://doi.org/10.1101/2023.02.27.530254

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