Endocannabinoid signaling across species – evolution and perspectives for drug discovery

Endocannabinoids are arachidonic acid derived lipids that show a broad range of biological effects in mammals. In the brain they are key modulators of neurotransmission and in the immune system they modulate acute and chronic inflammatory processes. Endocannabinoids have evolved early in evolution, prior to the classic mammalian cannabinoid receptors CB1 and CB2 [1] and seem to play important functions also in lower organisms [2], [3]. Currently, only two very distant plant taxa are known to exert psychoactive effects via CB1 receptors in vivo [4], but numerous non-psychoactive endocannabinoid system modulating natural products exist. In this lecture, I will discuss the biochemical convergence and how lipids from plants can inspire probe design and help to identify new biochemical pathways in mammals and how this can foster translational research. Results from an ongoing comprehensive “phylo-activity” screening program of plant extract libraries will highpoint the potential link between nutrition and the endocannabinoid system [5], warranting a more pharmacological inquiry into the relevance of plant secondary metabolites for human health.

• References

• 1 Gachet MS, Schubert A, Calarco S, Boccard J, Gertsch J. Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom. Sci Rep 2017; 7: 41177.
• 2 Chen AL, Lum KM, Lara-Gonzalez P, Ogasawara D, Petrascheck M, Bar-Peled L, Cravatt BF. Pharmacological convergence reveals a lipid pathway that regulates C. elegans lifespan. Nat Chem Biol 2019; 15: 453-462
• 3 Gertsch J. Scaffold and organism hopping with chemical probes. Nat Chem Biol 2019; 15: 428-429.
• 4 Chicca A, Schafroth MA, Reynoso-Moreno I, Erni R, Petrucci V, Carreira EM, Gertsch J. Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high. Sci Adv 2018; 4: eaat2166.
• 5 Gertsch J. Cannabimimetic phytochemicals in the diet - an evolutionary link to food selection and metabolic stress adaptation?. Br J Pharmacol 2017; June; 174 (11) 1464-1483.