:N-Arachidonoyl dopamine

{{short description|Chemical compound}}

{{DISPLAYTITLE:N-Arachidonoyl dopamine}}

{{chembox

| Verifiedfields = changed

| verifiedrevid = 477503651

| Name=N-Arachidonoyl dopamine

| ImageFile = N-Arachidonoyl dopamine.svg

| ImageSize = 220px

| ImageFile2 = N-arachidonoyl dopamine 3D BS.png

| ImageSize2 = 220px

| PIN = (5Z,8Z,11Z,14Z)-N-[2-(3,4-Dihydroxyphenyl)ethyl]icosa-5,8,11,14-tetraenamide

| OtherNames = NADA

|Section1={{Chembox Identifiers

| IUPHAR_ligand = 4261

| CASNo_Ref = {{cascite|changed|??}}

| CASNo = 199875-69-9

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 138921

| PubChem = 5282105

| SMILES = CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCC1=CC(=C(C=C1)O)O

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4445314

| InChI = 1/C28H41NO3/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-28(32)29-23-22-25-20-21-26(30)27(31)24-25/h6-7,9-10,12-13,15-16,20-21,24,30-31H,2-5,8,11,14,17-19,22-23H2,1H3,(H,29,32)/b7-6-,10-9-,13-12-,16-15-

| InChIKey = MVVPIAAVGAWJNQ-DOFZRALJBM

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C28H41NO3/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-28(32)29-23-22-25-20-21-26(30)27(31)24-25/h6-7,9-10,12-13,15-16,20-21,24,30-31H,2-5,8,11,14,17-19,22-23H2,1H3,(H,29,32)/b7-6-,10-9-,13-12-,16-15-

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = MVVPIAAVGAWJNQ-DOFZRALJSA-N

| MeSHName =

}}

|Section2={{Chembox Properties

| Formula = C₂₈H₄₁NO₃

| MolarMass = 439.63 g/mol

| Appearance =

| Density =

| MeltingPt =

| BoilingPt =

}}

|Section3={{Chembox Hazards

| MainHazards =

| FlashPt =

| AutoignitionPt =

}}

}}

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{{Cite journal|title = N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo|journal = The Biochemical Journal|date = 2000-11-01|issn = 0264-6021|pmc = 1221424|pmid = 11042139|pages = 817–824|volume = 351|first1 = T.|last1 = Bisogno|first2 = D.|last2 = Melck|first3 = null|last3 = Bobrov MYu|first4 = N. M.|last4 = Gretskaya|first5 = V. V.|last5 = Bezuglov|first6 = L.|last6 = De Petrocellis|first7 = V.|last7 = Di Marzo|doi=10.1042/bj3510817|issue=3}} and was subsequently identified as an endovanilloid (agonist for TRPV1) in 2002.{{cite journal | last1=Huang | first1=Susan M. | last2=Bisogno | first2=Tiziana | last3=Trevisani | first3=Marcello | last4=Al-Hayani | first4=Abdulmonem | last5=Petrocellis | first5=Luciano De | last6=Fezza | first6=Filomena | last7=Tognetto | first7=Michele | last8=Petros | first8=Timothy J. | last9=Krey | first9=Jocelyn F. | last10=Chu | first10=Constance J. | last11=Miller | first11=Jeffrey D. | last12=Davies | first12=Stephen N. | last13=Geppetti | first13=Pierangelo | last14=Walker | first14=J. Michael | last15=Marzo | first15=Vincenzo Di | title=An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors | journal=Proceedings of the National Academy of Sciences of the United States of America | volume=99 | issue=12 | date=2002-06-11 | pmid=12060783 | doi=10.1073/pnas.122196999| pmc=123079 | pages=8400–8405| bibcode=2002PNAS...99.8400H | doi-access=free }} NADA is an endogenous arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC₅₀ of approximately of 50 nM which makes it the putative endogenous TRPV1 agonist.

In mice, NADA was shown to induce the tetrad of physiological paradigms associated with cannabinoids: hypothermia, hypo-locomotion, catalepsy, and analgesia.{{Cite journal|title = Synthesis and biological evaluation of novel amides of polyunsaturated fatty acids with dopamine|journal = Bioorganic & Medicinal Chemistry Letters|date = 2001-02-26|issn = 0960-894X|pmid = 11229744|pages = 447–449|volume = 11|issue = 4|first1 = V.|last1 = Bezuglov|first2 = M.|last2 = Bobrov|first3 = N.|last3 = Gretskaya|first4 = A.|last4 = Gonchar|first5 = G.|last5 = Zinchenko|first6 = D.|last6 = Melck|first7 = T.|last7 = Bisogno|first8 = V.|last8 = Di Marzo|first9 = D.|last9 = Kuklev|doi=10.1016/s0960-894x(00)00689-2}}{{Cite journal|title = Pharmacology and stereoselectivity of structurally novel cannabinoids in mice|journal = The Journal of Pharmacology and Experimental Therapeutics|date = 1988-12-01|issn = 0022-3565|pmid = 2849657|pages = 1046–1051|volume = 247|issue = 3|first1 = P. J.|last1 = Little|first2 = D. R.|last2 = Compton|first3 = M. R.|last3 = Johnson|first4 = L. S.|last4 = Melvin|first5 = B. R.|last5 = Martin}} NADA has been found to play a regulatory role in both the peripheral and central nervous systems, and displays antioxidant and neuroprotectant properties.{{Cite journal|title = Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide|journal = British Journal of Pharmacology|date = 2004-04-01|issn = 0007-1188|pmc = 1574881|pmid = 15006899|pages = 1118–1130|volume = 141|issue = 7|doi = 10.1038/sj.bjp.0705711|first1 = Theodore J.|last1 = Price|first2 = Amol|last2 = Patwardhan|first3 = Armen N.|last3 = Akopian|first4 = Kenneth M.|last4 = Hargreaves|first5 = Christopher M.|last5 = Flores}}{{Cite journal|title = N-arachidonoyl-dopamine tunes synaptic transmission onto dopaminergic neurons by activating both cannabinoid and vanilloid receptors|journal = Neuropsychopharmacology|date = 2007-02-01|issn = 0893-133X|pmid = 16760924|pages = 298–308|volume = 32|issue = 2|doi = 10.1038/sj.npp.1301118|first1 = Silvia|last1 = Marinelli|first2 = Vincenzo|last2 = Di Marzo|first3 = Fulvio|last3 = Florenzano|first4 = Filomena|last4 = Fezza|first5 = Maria Teresa|last5 = Viscomi|first6 = Mario|last6 = van der Stelt|first7 = Giorgio|last7 = Bernardi|first8 = Marco|last8 = Molinari|first9 = Mauro|last9 = Maccarrone|doi-access = free}}{{Cite journal|title = 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|journal = The European Journal of Neuroscience|date = 2004-07-01|issn = 0953-816X|pmid = 15245490|pages = 175–184|volume = 20|issue = 1|doi = 10.1111/j.1460-9568.2004.03481.x|first1 = Devi R.|last1 = Sagar|first2 = Paul A.|last2 = Smith|first3 = Paul J.|last3 = Millns|first4 = Darren|last4 = Smart|first5 = David A.|last5 = Kendall|first6 = Victoria|last6 = Chapman|s2cid = 42626601}} NADA has also been implicated in smooth muscle contraction and vasorelaxation in blood vessels.{{Cite journal|title = Antioxidant and neuroprotective properties of N-arachidonoyldopamine|journal = Neuroscience Letters|date = 2008-01-24|issn = 0304-3940|pmid = 18069125|pages = 6–11|volume = 431|issue = 1|doi = 10.1016/j.neulet.2007.11.010|first1 = Mikhail Yu|last1 = Bobrov|first2 = Anatoly A.|last2 = Lizhin|first3 = Ekaterina L.|last3 = Andrianova|first4 = Natalia M.|last4 = Gretskaya|first5 = Lidia E.|last5 = Frumkina|first6 = Leonid G.|last6 = Khaspekov|first7 = Vladimir V.|last7 = Bezuglov|s2cid = 23436811}}{{Cite journal|title = Capsaicin-like effects of N-arachidonoyl-dopamine in the isolated guinea pig bronchi and urinary bladder|journal = European Journal of Pharmacology|date = 2003-08-15|issn = 0014-2999|pmid = 12954366|pages = 107–114|volume = 475|issue = 1–3|first1 = Selena|last1 = Harrison|first2 = Luciano|last2 = De Petrocellis|first3 = Marcello|last3 = Trevisani|first4 = Francesca|last4 = Benvenuti|first5 = Maurizio|last5 = Bifulco|first6 = Pierangelo|last6 = Geppetti|first7 = Vincenzo|last7 = Di Marzo|doi=10.1016/s0014-2999(03)02114-9}}{{Cite journal|title = Characterisation of the vasorelaxant properties of the novel endocannabinoid N-arachidonoyl-dopamine (NADA)|journal = British Journal of Pharmacology|date = 2004-03-01|issn = 0007-1188|pmc = 1574254|pmid = 14769783|pages = 803–812|volume = 141|issue = 5|doi = 10.1038/sj.bjp.0705643|first1 = Saoirse E.|last1 = O'Sullivan|first2 = David A.|last2 = Kendall|first3 = Michael D.|last3 = Randall}}{{Cite journal|title = Time-dependent vascular effects of Endocannabinoids mediated by peroxisome proliferator-activated receptor gamma (PPARγ)|journal = PPAR Research|date = 2009-01-01|issn = 1687-4757|pmc = 2676321|pmid = 19421417|pages = 425289|volume = 2009|doi = 10.1155/2009/425289|first1 = Saoirse E.|last1 = O'Sullivan|first2 = David A.|last2 = Kendall|first3 = Michael D.|last3 = Randall|doi-access = free}} 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).{{Cite journal|title = Opposite effects of anandamide and N-arachidonoyl dopamine in the regulation of prostaglandin E and 8-iso-PGF formation in primary glial cells|journal = Journal of Neurochemistry|date = 2009-04-01|issn = 1471-4159|pmid = 19200337|pages = 452–464|volume = 109|issue = 2|doi = 10.1111/j.1471-4159.2009.05966.x|first1 = Carmen M.|last1 = Navarrete|first2 = Bernd L.|last2 = Fiebich|first3 = Amaya García|last3 = de Vinuesa|first4 = Sandra|last4 = Hess|first5 = Antonio C. P.|last5 = de Oliveira|first6 = Eduardo|last6 = Candelario-Jalil|first7 = Francisco J.|last7 = Caballero|first8 = Marco A.|last8 = Calzado|first9 = Eduardo|last9 = Muñoz|s2cid = 205620351|doi-access = }}{{Cite journal|title = Endogenous N-acyl-dopamines induce COX-2 expression in brain endothelial cells by stabilizing mRNA through a p38 dependent pathway|journal = Biochemical Pharmacology|date = 2010-06-15|issn = 1873-2968|pmid = 20206142|pages = 1805–1814|volume = 79|issue = 12|doi = 10.1016/j.bcp.2010.02.014|first1 = Carmen M.|last1 = Navarrete|first2 = Moisés|last2 = Pérez|first3 = Amaya García|last3 = de Vinuesa|first4 = Juan A.|last4 = Collado|first5 = Bernd L.|last5 = Fiebich|first6 = Marco A.|last6 = Calzado|first7 = Eduardo|last7 = Muñoz}}{{Cite journal|title = Immunosuppressive activity of endovanilloids: N-arachidonoyl-dopamine inhibits activation of the NF-kappa B, NFAT, and activator protein 1 signaling pathways|journal = Journal of Immunology|date = 2004-02-15|issn = 0022-1767|pmid = 14764703|pages = 2341–2351|volume = 172|issue = 4|first1 = Rocío|last1 = Sancho|first2 = Antonio|last2 = Macho|first3 = Laureano|last3 = de La Vega|first4 = Marco A.|last4 = Calzado|first5 = Bernd L.|last5 = Fiebich|first6 = Giovanni|last6 = Appendino|first7 = Eduardo|last7 = Muñoz|doi=10.4049/jimmunol.172.4.2341|doi-access = free}} 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.{{Cite journal|title = The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells|journal = The Journal of Biological Chemistry|date = 2014-05-09|issn = 1083-351X|pmc = 4036321|pmid = 24644287|pages = 13079–13100|volume = 289|issue = 19|doi = 10.1074/jbc.M113.536953|first1 = Kevin|last1 = Wilhelmsen|first2 = Samira|last2 = Khakpour|first3 = Alphonso|last3 = Tran|first4 = Kayla|last4 = Sheehan|first5 = Mark|last5 = Schumacher|first6 = Fengyun|last6 = Xu|first7 = Judith|last7 = Hellman|doi-access = free}} It can increase the TRPV1-mediated release of substance P and calcitonin gene-related peptide (CGRP) in rat dorsal spinal cord slices. Furthermore, NADA also displays inhibitory activity in HIV-1 replication assays.{{Cite journal|title = Mechanisms of HIV-1 inhibition by the lipid mediator N-arachidonoyldopamine|journal = Journal of Immunology|date = 2005-09-15|issn = 0022-1767|pmid = 16148147|pages = 3990–3999|volume = 175|issue = 6|first1 = Rocío|last1 = Sancho|first2 = Laureano|last2 = de la Vega|first3 = Antonio|last3 = Macho|first4 = Giovanni|last4 = Appendino|first5 = Vincenzo|last5 = Di Marzo|first6 = Eduardo|last6 = Muñoz|doi=10.4049/jimmunol.175.6.3990|doi-access = free}} Finally, NADA can prevent the degranulation and release of TNF from RBL- 2H3 mast cells treated with an IgE-antigen complex.{{Cite journal|title = Inhibitory effect of N-Acyl dopamines on IgE-mediated allergic response in RBL-2H3 cells|journal = Lipids|date = 2013-04-01|issn = 1558-9307|pmid = 23377981|pages = 383–393|volume = 48|issue = 4|doi = 10.1007/s11745-013-3758-6|first1 = Jae-Myung|last1 = Yoo|first2 = Eun Seok|last2 = Park|first3 = Mee Ree|last3 = Kim|first4 = Dai-Eun|last4 = Sok|s2cid = 3995567}} 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.{{cite journal | title=The biosynthesis of N-arachidonoyl dopamine (NADA), a putative endocannabinoid and endovanilloid, via conjugation of arachidonic acid with dopamine | journal=Prostaglandins, Leukotrienes and Essential Fatty Acids | volume=81 | issue=4 | date=2009-10-01 | issn=0952-3278 | doi=10.1016/j.plefa.2009.05.026 | pmid=19570666 | pages=291–301 | ref={{sfnref | Prostaglandins, Leukotrienes and Essential Fatty Acids | 2009}} | last1 = Shu-Jung Hu | first1 = Sherry | last2 = Bradshaw | first2 = Heather B. | last3 = Benton | first3 = Valery M. | last4 = Shih-Chieh Chen | first4 = Jay | last5 = Huang | first5 = Susan M. | last6 = Minassi | first6 = Alberto | last7 = Bisogno | first7 = Tiziana | last8 = Masuda | first8 = Kim | last9 = Tan | first9 = Bo | last10 = Roskoski | first10 = Robert | last11 = Cravatt | first11 = Benjamin F. | last12 = Di Marzo | first12 = Vincenzo | last13 = Walker | first13 = J. Michael| pmc=2757501 }} 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.).{{cite journal | last1=Pajouhesh | first1=H | last2=Hancock | first2=A J | title=Synthesis of cyclopentano-N-methylphosphatidylethanolamines: aminolysis during the use of methylamine. | journal=Journal of Lipid Research | volume=25 | issue=3 | date=1984-03-01 | issn=0022-2275 | pmid=6726084 | pages=310–312 | doi=10.1016/S0022-2275(20)37828-7 | url=http://www.jlr.org/content/25/3/310.abstract| access-date=2017-12-15| doi-access=free }}