Discovery of potent chromone-based autotaxin inhibitors inspired by cannabinoids

Eymery, Mathias Christophe; Nguyen, Kim-Anh; Basu, Shibom; Hausmann, Jens; Tran-Nguyen, Viet-Khoa; Seidel, Hans Peter; Gutierrez, Lola; Boumendjel, Ahcène; McCarthy, Andrew Aloysius

doi:10.1016/j.ejmech.2023.115944

Cited by 1 publication

(2 citation statements)

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“…Indeed, inhibitors might need to be taken several times a day to maintain ATX inhibition and subsequently reduce LPA production. The development of cannabinoid-inspired ATX inhibitors might be interesting from this point of view since their lipidic structure allows potential deposits in fatty tissues and lipid carrier proteins to prolong the limited inhibition following their administration [ 44 , 66 , 67 ].…”

Section: Future Directionsmentioning

confidence: 99%

“…More recent research linked ATX to neurological diseases, with the detection and the characterization of the ATX-γ isoform in the central nervous system [ 43 , 44 ]. LPA has been widely studied for its pleiotropic effect but also for its specific role in triggering neurological diseases, such as neuropathic pain, Alzheimer’s disease, glioblastoma multiform, schizophrenia, multiple sclerosis, and traumatic brain injuries [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

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Linking the Autotaxin-LPA Axis to Medicinal Cannabis and the Endocannabinoid System

Eymery,

Boumendjel,

McCarthy

et al. 2024

IJMS

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Over the past few decades, many current uses for cannabinoids have been described, ranging from controlling epilepsy to neuropathic pain and anxiety treatment. Medicines containing cannabinoids have been approved by both the FDA and the EMA for the control of specific diseases for which there are few alternatives. However, the molecular-level mechanism of action of cannabinoids is still poorly understood. Recently, cannabinoids have been shown to interact with autotaxin (ATX), a secreted lysophospholipase D enzyme responsible for catalyzing lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a pleiotropic growth factor that interacts with LPA receptors. In addition, a high-resolution structure of ATX in complex with THC has recently been published, accompanied by biochemical studies investigating this interaction. Due to their LPA-like structure, endocannabinoids have been shown to interact with ATX in a less potent manner. This finding opens new areas of research regarding cannabinoids and endocannabinoids, as it could establish the effect of these compounds at the molecular level, particularly in relation to inflammation, which cannot be explained by the interaction with CB1 and CB2 receptors alone. Further research is needed to elucidate the mechanism behind the interaction between cannabinoids and endocannabinoids in humans and to fully explore the therapeutic potential of such approaches.

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Section: Future Directionsmentioning

confidence: 99%