N-Arachidonoyl dopamine explained

N-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 receptor) in 2000[1] and was subsequently identified as an endovanilloid (agonist for TRPV1) in 2002.[2] NADA is an endogenous arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum.[2] It activates the TRPV1 channel with an EC50 of approximately of 50 nM which makes it the putative endogenous TRPV1 agonist.[2]

In mice, NADA was shown to induce the tetrad of physiological paradigms associated with cannabinoids: hypothermia, hypo-locomotion, catalepsy, and analgesia.[3] [4] NADA has been found to play a regulatory role in both the peripheral and central nervous systems, and displays antioxidant and neuroprotectant properties.[2] [5] [6] [7] NADA has also been implicated in smooth muscle contraction and vasorelaxation in blood vessels.[8] [9] [10] [11] Additionally, NADA has been observed to suppress inflammatory activation of human Jurkat T cells and to inhibit the release of prostaglandin E2 (PGE2) from lipopolysaccharide (LPS)-activated astrocytes, microglia and mouse brain ECs (MEC-Brain).[12] [13] [14] NADA also promotes the inflammatory resolution of human endothelial cells activated by both endogenous (i.e. TNF) and exogenous (i.e. bacterial derived LPS (TLR4 agonist) and FSL-1 (TLR2/6 agonist)) inflammatory mediators.[15] It can increase the TRPV1-mediated release of substance P and calcitonin gene-related peptide (CGRP) in rat dorsal spinal cord slices.[2] Furthermore, NADA also displays inhibitory activity in HIV-1 replication assays.[16] Finally, NADA can prevent the degranulation and release of TNF from RBL- 2H3 mast cells treated with an IgE-antigen complex.[17] Together, these studies show that physiological functions attributed to NADA are multifaceted, and include the ability to modulate the immune response.

The biosynthetic pathway of N-arachindonoyldopamine is not well understood. It has been proposed to be conjugated from arachidonoyl-CoA or arachidonoyl phospholipids and dopamine, but in vitro experiments do not support this theory.[18] However, the indirect biosynthesis of phospholipid esters with dopamine may be possible, as dopamine can induce the aminolysis of the glycerol-fatty acid bonds in phospholipid chains (arachidonoyl, palmitoyl, linoleyl, etc.).[19]

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Notes and References

  1. N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. The Biochemical Journal. 2000-11-01. 0264-6021. 1221424. 11042139. 817–824. 351. T.. Bisogno. D.. Melck. null. Bobrov MYu. N. M.. Gretskaya. V. V.. Bezuglov. L.. De Petrocellis. V.. Di Marzo. 10.1042/bj3510817. 3.
  2. Huang . Susan M. . Bisogno . Tiziana . Trevisani . Marcello . Al-Hayani . Abdulmonem . Petrocellis . Luciano De . Fezza . Filomena . Tognetto . Michele . Petros . Timothy J. . Krey . Jocelyn F. . Chu . Constance J. . Miller . Jeffrey D. . Davies . Stephen N. . Geppetti . Pierangelo . Walker . J. Michael . Marzo . Vincenzo Di . An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors . Proceedings of the National Academy of Sciences of the United States of America . 99 . 12 . 2002-06-11 . 12060783 . 10.1073/pnas.122196999. 123079 . 8400–8405. 2002PNAS...99.8400H . free .
  3. Synthesis and biological evaluation of novel amides of polyunsaturated fatty acids with dopamine. Bioorganic & Medicinal Chemistry Letters. 2001-02-26. 0960-894X. 11229744. 447–449. 11. 4. V.. Bezuglov. M.. Bobrov. N.. Gretskaya. A.. Gonchar. G.. Zinchenko. D.. Melck. T.. Bisogno. V.. Di Marzo. D.. Kuklev. 10.1016/s0960-894x(00)00689-2.
  4. Pharmacology and stereoselectivity of structurally novel cannabinoids in mice. The Journal of Pharmacology and Experimental Therapeutics. 1988-12-01. 0022-3565. 2849657. 1046–1051. 247. 3. P. J.. Little. D. R.. Compton. M. R.. Johnson. L. S.. Melvin. B. R.. Martin.
  5. Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide. British Journal of Pharmacology. 2004-04-01. 0007-1188. 1574881. 15006899. 1118–1130. 141. 7. 10.1038/sj.bjp.0705711. Theodore J.. Price. Amol. Patwardhan. Armen N.. Akopian. Kenneth M.. Hargreaves. Christopher M.. Flores.
  6. N-arachidonoyl-dopamine tunes synaptic transmission onto dopaminergic neurons by activating both cannabinoid and vanilloid receptors. Neuropsychopharmacology. 2007-02-01. 0893-133X. 16760924. 298–308. 32. 2. 10.1038/sj.npp.1301118. Silvia. Marinelli. Vincenzo. Di Marzo. Fulvio. Florenzano. Filomena. Fezza. Maria Teresa. Viscomi. Mario. van der Stelt. Giorgio. Bernardi. Marco. Molinari. Mauro. Maccarrone. free.
  7. TRPV1 and CB(1) receptor-mediated effects of the endovanilloid/endocannabinoid N-arachidonoyl-dopamine on primary afferent fibre and spinal cord neuronal responses in the rat. The European Journal of Neuroscience. 2004-07-01. 0953-816X. 15245490. 175–184. 20. 1. 10.1111/j.1460-9568.2004.03481.x. Devi R.. Sagar. Paul A.. Smith. Paul J.. Millns. Darren. Smart. David A.. Kendall. Victoria. Chapman. 42626601.
  8. Antioxidant and neuroprotective properties of N-arachidonoyldopamine. Neuroscience Letters. 2008-01-24. 0304-3940. 18069125. 6–11. 431. 1. 10.1016/j.neulet.2007.11.010. Mikhail Yu. Bobrov. Anatoly A.. Lizhin. Ekaterina L.. Andrianova. Natalia M.. Gretskaya. Lidia E.. Frumkina. Leonid G.. Khaspekov. Vladimir V.. Bezuglov. 23436811.
  9. Capsaicin-like effects of N-arachidonoyl-dopamine in the isolated guinea pig bronchi and urinary bladder. European Journal of Pharmacology. 2003-08-15. 0014-2999. 12954366. 107–114. 475. 1–3. Selena. Harrison. Luciano. De Petrocellis. Marcello. Trevisani. Francesca. Benvenuti. Maurizio. Bifulco. Pierangelo. Geppetti. Vincenzo. Di Marzo. 10.1016/s0014-2999(03)02114-9.
  10. Characterisation of the vasorelaxant properties of the novel endocannabinoid N-arachidonoyl-dopamine (NADA). British Journal of Pharmacology. 2004-03-01. 0007-1188. 1574254. 14769783. 803–812. 141. 5. 10.1038/sj.bjp.0705643. Saoirse E.. O'Sullivan. David A.. Kendall. Michael D.. Randall.
  11. Time-dependent vascular effects of Endocannabinoids mediated by peroxisome proliferator-activated receptor gamma (PPARγ). PPAR Research. 2009-01-01. 1687-4757. 2676321. 19421417. 425289. 2009. 10.1155/2009/425289. Saoirse E.. O'Sullivan. David A.. Kendall. Michael D.. Randall. free.
  12. Opposite effects of anandamide and N-arachidonoyl dopamine in the regulation of prostaglandin E and 8-iso-PGF formation in primary glial cells. Journal of Neurochemistry. 2009-04-01. 1471-4159. 19200337. 452–464. 109. 2. 10.1111/j.1471-4159.2009.05966.x. Carmen M.. Navarrete. Bernd L.. Fiebich. Amaya García. de Vinuesa. Sandra. Hess. Antonio C. P.. de Oliveira. Eduardo. Candelario-Jalil. Francisco J.. Caballero. Marco A.. Calzado. Eduardo. Muñoz. 205620351.
  13. Endogenous N-acyl-dopamines induce COX-2 expression in brain endothelial cells by stabilizing mRNA through a p38 dependent pathway. Biochemical Pharmacology. 2010-06-15. 1873-2968. 20206142. 1805–1814. 79. 12. 10.1016/j.bcp.2010.02.014. Carmen M.. Navarrete. Moisés. Pérez. Amaya García. de Vinuesa. Juan A.. Collado. Bernd L.. Fiebich. Marco A.. Calzado. Eduardo. Muñoz.
  14. Immunosuppressive activity of endovanilloids: N-arachidonoyl-dopamine inhibits activation of the NF-kappa B, NFAT, and activator protein 1 signaling pathways. Journal of Immunology. 2004-02-15. 0022-1767. 14764703. 2341–2351. 172. 4. Rocío. Sancho. Antonio. Macho. Laureano. de La Vega. Marco A.. Calzado. Bernd L.. Fiebich. Giovanni. Appendino. Eduardo. Muñoz. 10.4049/jimmunol.172.4.2341. free.
  15. The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells. The Journal of Biological Chemistry. 2014-05-09. 1083-351X. 4036321. 24644287. 13079–13100. 289. 19. 10.1074/jbc.M113.536953. Kevin. Wilhelmsen. Samira. Khakpour. Alphonso. Tran. Kayla. Sheehan. Mark. Schumacher. Fengyun. Xu. Judith. Hellman. free.
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  18. The biosynthesis of N-arachidonoyl dopamine (NADA), a putative endocannabinoid and endovanilloid, via conjugation of arachidonic acid with dopamine . Prostaglandins, Leukotrienes and Essential Fatty Acids . 81 . 4 . 2009-10-01 . 0952-3278 . 10.1016/j.plefa.2009.05.026 . 19570666 . 291–301 . . Shu-Jung Hu . Sherry . Bradshaw . Heather B. . Benton . Valery M. . Shih-Chieh Chen . Jay . Huang . Susan M. . Minassi . Alberto . Bisogno . Tiziana . Masuda . Kim . Tan . Bo . Roskoski . Robert . Cravatt . Benjamin F. . Di Marzo . Vincenzo . Walker . J. Michael. 2757501 .
  19. Pajouhesh . H . Hancock . A J . Synthesis of cyclopentano-N-methylphosphatidylethanolamines: aminolysis during the use of methylamine. . Journal of Lipid Research . 25 . 3 . 1984-03-01 . 0022-2275 . 6726084 . 310–312 . 10.1016/S0022-2275(20)37828-7 . 2017-12-15. free .

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