Endocannabinoid reuptake inhibitors (eCBRIs), also called cannabinoid reuptake inhibitors (CBRIs), are drugs which limit the reabsorption of endocannabinoid neurotransmitters by the releasing neuron.[1][2]


The method of transport of endocannabinoids through the cell membrane and cytoplasm to their respective degradation enzymes has been rigorously debated for nearly two decades, and a putative endocannabinoid membrane transporter was proposed.[3] However, as lipophilic molecules endocannabinoids readily pass through the cell lipid bilayer without assistance and would more likely need a chaperone through the cytoplasm to the endoplasmic reticulum where the enzyme FAAH is located. More recently fatty acid-binding proteins (FABPs) and heat shock proteins (Hsp70s) have been described and verified as such chaperones, and their inhibitors have been synthesized.[1][4] The inhibition of endocannabinoid reuptake raises the amount of those neurotransmitters available in the synaptic cleft and therefore increases neurotransmission. Following the increase of neurotransmission in the endocannabinoid system is the stimulation of its functions which, in humans, include: suppression of pain perception (analgesia), increased appetite, mood elevation and inhibition of short-term memory.[5][6]

Examples of eCBRIs

See also


  1. ^ a b Berger WT, Ralph BP, Kaczocha M, Sun J, Balius TE, Rizzo RC, Haj-Dahmane S, Ojima I, Deutsch DG (2012). "Targeting fatty acid binding protein (FABP) anandamide transporters - a novel strategy for development of anti-inflammatory and anti-nociceptive drugs". PLOS ONE. 7 (12): e50968. Bibcode:2012PLoSO...750968B. doi:10.1371/journal.pone.0050968. PMC 3517626. PMID 23236415.
  2. ^ a b Costa B, Siniscalco D, Trovato AE, Comelli F, Sotgiu ML, Colleoni M, Maione S, Rossi F, Giagnoni G (2006). "AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain". Br. J. Pharmacol. 148 (7): 1022–32. doi:10.1038/sj.bjp.0706798. PMC 1751928. PMID 16770320.
  3. ^ Nicolussi, Simon; Gertsch, Jürg (2015). "Endocannabinoid Transport Revisited". Vitamins & Hormones. 98 (14): 441–485. doi:10.1016/bs.vh.2014.12.011. PMID 25817877. Retrieved 2021-01-17.
  4. ^ Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-Agro, A.; Maccarrone, M. (2009). "Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins". Chemistry & Biology. 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477.
  5. ^ "Endocannabinoid System".
  6. ^ Chicca, Andrea; Nicolussi, Simon; Bartholomäus, Ruben; Blunder, Martina; Aparisi Rey, Alejandro; Petrucci, Vanessa; Reynoso-Moreno, Ines del Carmen; Viveros-Paredes, Juan Manuel; Dalghi Gens, Marianela; Lutz, Beat; Schiöth, Helgi B.; Soeberdt, Michael; Abels, Christoph; Charles, Roch-Philippe; Altmann, Karl-Heinz; Gertsch, Jürg (20 June 2017). "Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake". Proceedings of the National Academy of Sciences of the United States of America. 114 (25): E5006–E5015. Bibcode:2017PNAS..114E5006C. doi:10.1073/pnas.1704065114. ISSN 0027-8424. PMC 5488949. PMID 28584105.
  7. ^ Glaser ST, Kaczocha M, Deutsch DG (Aug 2005). "Anandamide transport: a critical review". Life Sci. 77 (14): 1584–604. doi:10.1016/j.lfs.2005.05.007. PMID 15979096.
  8. ^ Moore SA, Nomikos GG, Dickason-Chesterfield AK, Schober DA, Schaus JM, Ying BP, Xu YC, Phebus L, Simmons RM, Li D, Iyengar S, Felder CC (2005). "Identification of a high-affinity binding site involved in the transport of endocannabinoids.". Proceedings of the National Academy of Sciences. 102 (49): 17852–7. doi:10.1073/pnas.0507470102. PMC 1295594. PMID 16314570.
  9. ^ Nicolussi S, Viveros-Paredes JM, Gachet MS, Rau M, Flores-Soto ME, Blunder M, Gertsch J (Feb 2014). "Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice". Pharmacol. Res. 80: 52–65. doi:10.1016/j.phrs.2013.12.010. PMID 24412246.
  10. ^ Chicca A, Nicolussi S, Bartholomäus R, Blunder M, Aparisi Rey A, Petrucci V, Reynoso-Moreno ID, Viveros-Paredes JM, Dalghi Gens M, Lutz B, Schiöth HB, Soeberdt M, Abels C, Charles RP, Altmann KH, Gertsch J (2017). "Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake". Proc Natl Acad Sci U S A. 55 (25): E5006–E5015. Bibcode:2017PNAS..114E5006C. doi:10.1073/pnas.1704065114. PMC 5488949. PMID 28584105.
  11. ^ Nicolussi S, Chicca A, Soeberdt M, Abels C, Viveros.Paredes JM, Aparisi-Rey A, Lutz B, Gertsch J. WOBE437 - Prototype of a novel class of potent, selective endocannabinoid reuptake inhibitors. BPS 6th Eur Workshop on Cannabinoid Research 2013.