Endocannabinoid reuptake inhibitors

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Endocannabinoid reuptake inhibitors ( eCBRIs from English endocannabinoid reuptake inhibitors ) is the name for substances that have been sought since around 2000 to enhance the desired effects of endogenous cannabinoids - for example in pain therapy .

The model for this was the success with classic neurotransmitters , such as the use of serotonin reuptake inhibitors . However, since the mechanisms of classic neurotransmitters and endocannabinoids differ fundamentally in many ways, the search for possible endocannabinoid reuptake inhibitors turned out to be extremely complex.

Although substances were soon found that had intensifying effects, it remained controversial whether there was even a transport system for endocannabinoids that could be inhibited by the substances. In contrast to classic neurotransmitters, endocannabinoids do not require any transporters in the cell membrane of a nerve cell . It was assumed, however, that there could be transporters in the cell that transport endocannabinoids from the inside of the cell membrane into the interior of the cell and thereby support the uptake into the cell - for the purpose of degradation there. The inhibition of such a transporter would increase the amount of endocannabinoids as signal transmitters (at the synapse ) and thus their neuroactive effect.

In 2009 a candidate for such an intracellular transporter was found for the first time. In 2013, however, it turned out that this was not the expected transporter. At the moment (as of February 2016) it is completely open whether there is even a transport system for endocannabinoids.

Active ingredients

Substances that partially increased the effect of endocannabinoids in rats and mice and were at times considered to be possible endocannabinoid reuptake inhibitors are N- arachidonoylphenolamine (AM404), VDM-11 , LY-2183240 , URB597 , AM1172 , O-2093 , OMDM-2 , UCM-707 , Guineensin , WOBE437 and RX-055 .

See also

Individual evidence

  1. ↑ K. Leung, MW Elmes, ST Glaser, DG Deutsch, M. Kaczocha: Role of FAAH-like anandamide transporter in anandamide inactivation. In: PloS one. Volume 8, number 11, 2013, p. E79355, doi : 10.1371 / journal.pone.0079355 , PMID 24223930 , PMC 3817039 (free full text).
  2. ↑ B. Costa, D. Siniscalco, AE Trovato, F. Comelli, ML Sotgiu, M. Colleoni, S. Maione, F. Rossi, G. Giagnoni: AM404, an inhibitor of anandamide uptake, prevents pain behavior and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. In: British journal of pharmacology. Volume 148, number 7, August 2006, pp. 1022-1032, doi : 10.1038 / sj.bjp.0706798 , PMID 16770320 , PMC 1751928 (free full text).
  3. ^ SA Moore, GG Nomikos, AK Dickason-Chesterfield, DA Schober, JM Schaus, BP Ying, YC Xu, L. Phebus, RM Simmons, D. Li, S. Iyengar, CC Felder: Identification of a high-affinity binding site involved in the transport of endocannabinoids. In: Proceedings of the National Academy of Sciences . Volume 102, number 49, December 2005, pp. 17852-17857, doi : 10.1073 / pnas.0507470102 , PMID 16314570 , PMC 1295594 (free full text).
  4. ↑ ST Glaser, M. Kaczocha, DG German: Anandamide transport: a critical review. In: Life sciences. Volume 77, Number 14, August 2005, pp. 1584-1604, doi : 10.1016 / j.lfs.2005.05.007 , PMID 15979096 .
  5. Jump up ↑ S. Nicolussi, JM Viveros-Paredes, MS Gachet, M. Rau, ME Flores-Soto, M. Blunder, J. Gertsch: Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB / c mice. In: Pharmacological research. Volume 80, February 2014, pp. 52-65, doi : 10.1016 / j.phrs.2013.12.010 , PMID 24412246 .
  6. ↑ A. Chicca, S. Nicolussi, R. Bartholomäus, M. Blunder, A. Aparisi Rey, V. Petrucci, ID Reynoso-Moreno, JM Viveros-Paredes, M. Dalghi Gens, B. Lutz, HB Schiöth, M. Soeberdt, C. Abels, RP Charles, KH Altmann, J. Gertsch: Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake. In: Proceedings of the National Academy of Sciences . Volume 114, number 25, 06 2017, pp. E5006 – E5015, doi : 10.1073 / pnas.1704065114 , PMID 28584105 , PMC 5488949 (free full text).
  7. ↑ 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.