endocannabinoid reuptake

Anandamide (arachidonoyl ethanolamide; AEA) is an endogenous lipid with cannabinergic activity; along with 2-arachidonoyl glycerol, it forms part of the endocannabinoid system. AEA undergoes reuptake into neurons by a facilitated process. Controversy exists as to whether there is a specific AEA transporter, or instead the uptake process is simply driven by hydrolysis of AEA by intracellular fatty acyl amide hydrolase (FAAH). CAY10412 is an analog of AEA that has no intrinsic binding affinity for either CB1 or CB2 receptors. It is a potent inhibitor of AEA reuptake in U937 lymphoma cells, with an IC50 of 3 μM. CAY10412 could be a useful tool for distinguishing the competing transporter theories. The pharmacology of CAY10412 is largely unexplored; it may enhance endocannabinoid signalling by augmenting endocannabinoid concentrations.

AM404 is an endocannabinoid reuptake inhibitor, a TRPV(1) activator, a paracetamol metabolite, with neuroprotective and anticancer activity that blocks anandamide transport. AM404 inhibits NFAT and NF-kappaB signaling pathways and impairs migration and invasiveness of neuroblastoma cells, preventing prostaglandin synthesis in activated microglia by inhibiting COX activity.

WOBE437 is a selective endocannabinoid reuptake inhibitor which reduces disease progression in a mouse model of multiple sclerosis

2-Arachidonoyl glycerol (2-AG), a natural endocannabinoid ligand for the CB1 receptor, was isolated from porcine brain and characterized. Its congener, 2-linoleoyl glycerol (2-LG), which has a linoleoyl group instead of an arachidonoyl group, also exists alongside 2-AG in vivo. While 2-LG exhibits low intrinsic activity, it enhances the activity of 2-AG and other endocannabinoids through an entourage effect, attributed to the inhibition of breakdown and reuptake pathways that typically decrease endocannabinoid levels post-release.