Bioactive Oleic Derivatives of Dopamine: A Review of the Therapeutic Potential

  • Mieczyslaw PokorskiEmail author
  • Dominika Zajac
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1096)


Lipid derivatives of dopamine are a novel class of compounds raising a research interest due to the potential of their being a vehicle for dopamine delivery to the brain. The aim of the present paper is to review the main features of the two most prominent bioactive members of this family, namely, N-oleoyl-dopamine (OLDA) and 3′-O-methyl-N-oleoyl-dopamine (OMe-OLDA), with emphasis on the possible therapeutic properties.


Brain Dopamine receptor Lipid derivatives of dopamine Therapeutic potential TRPV1 receptors 



The dopamides reviewed in this article were synthetized in the Laboratory of Natural Products Chemistry, The Faculty of Chemistry, University of Warsaw. We remain appreciative of Dr. Zbigniew Czarnocki and Piotr Roszkowski’s dexterity in the elaboration of de novo synthesis of the dopamides, and we are thankful for the provision of the compounds for our biological studies. We also thank Dr. Agnieszka Stasińska for giving a hand in some of the experiments described herein.

Conflicts of Interest

The authors of this article are the inventors of the European (EP 2324824) and the US patents (US 8697898) covering the potential medical applications of OLDA and OMe-OLDA. The patent procedures were in part financed by the EU Innovative Economy grant POIG 1.3.2.-14–047/11.


  1. Akimov MG, Nazimov IV, Gretskaya NM, Zinchenko GN, Bezuglov VV (2009) Sulfation of N-acyl dopamines in rat tissues. Biochem Mosc 74:681–685CrossRefGoogle Scholar
  2. Alachkar A, Brotchie JM, Jones OT (2010) Binding of dopamine and 3-methoxytyramine as L-DOPA metabolites to human alpha2-adrenergic and dopaminergic receptors. Neurosci Res 67:245–249CrossRefPubMedGoogle Scholar
  3. Almaghrabi SY, Geraghty DP, Ahuja KD, Adams MJ (2014) Vanilloid-like agents inhibit aggregation of human platelets. Thromb Res 134(2):412–417CrossRefPubMedGoogle Scholar
  4. Almasi R, Szoke E, Bolcskei K, Varga A, Riedl Z, Sandor Z, Szolcsanyi J, Petho G (2008) Actions of 3-methyl-N-oleoyldopamine, 4-methyl-N-oleoyldopamine and N-oleoylethanolamide on the rat TRPV1 receptor in vitro and in vivo. Life Sci 82:644–651CrossRefPubMedGoogle Scholar
  5. Bezuglov V, Bobrov M, Gretskaya N, Gonchar A, Zinchenko G, Melck D, Bisogno T, Di Marzo V, Kuklev D, Rossi JC, Vidal JP, Durand T (2001) Synthesis and biological evaluation of novel amides of polyunsaturated fatty acids with dopamine. Bioorg Med Chem Lett 11:447–449CrossRefPubMedGoogle Scholar
  6. Bisogno T, Melck D, Bobrov M, Gretskaya N, Bezuglov V, De Petrocellis L, Di Marzo L (2000) N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem J 351(Pt 3):817–824CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bobrov MY, Lizhin AA, Andrianova EL, Gretskaya NM, Frumkina LE, Khaspekov LG, Bezuglov VV (2008) Antioxidant and neuroprotective properties of N-arachidonoyldopamine. Neurosci Lett 431:6–11CrossRefPubMedGoogle Scholar
  8. Bolcskei K, Tékus V, Dézsi L, Szolcsanyi J, Petho G (2010) Antinociceptive desensitizing actions of TRPV1 receptor agonists capsaicin, resiniferatoxin and N-oleoyldopamine as measured by determination of the noxious heat and cold thresholds in the rat. Eur J Pain 14:480–486CrossRefPubMedGoogle Scholar
  9. Butelman ER, Harris TJ, Kreek MJ (2004) Antiallodynic effects of loperamide and fentanyl against topical capsaicin-induced allodynia in unanesthetized primates. J Pharmacol Exp Ther 311:155–163CrossRefPubMedGoogle Scholar
  10. Chu C, Huang S, De Petrocellis L, Bisogno T, Ewing S, Miller J, Zipkin R, Daddario N, Appendino G, Di Marzo V, Walker J (2003) N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia. J Biol Chem 278:13633–13639CrossRefPubMedGoogle Scholar
  11. Chu ZL, Carroll C, Chen R, Alfonso J, Gutierrez V, He H, Lucman A, Xing C, Sebring K, Zhou J, Wagner B, Unett D, Jones RM, Behan DP, Leonard J (2010) N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119. Mol Endocrinol 24:161–170CrossRefPubMedPubMedCentralGoogle Scholar
  12. Czarnocki Z, Matuszewska I, Matuszewska M (1998) Highly efficient synthesis of fatty acids dopamides. Org Prep Proced Int 30:699–702CrossRefGoogle Scholar
  13. Daily D, Barzilai A, Offen D, Kamsler A, Melamed E, Ziv I (1999) The involvement of p53 in dopamine-induced apoptosis of cerebellar granule neurons and leukemic cells overexpressing p53. Cell Mol Neurobiol 19:261–276CrossRefPubMedGoogle Scholar
  14. De Petrocellis L, Chu CJ, Schiano Moriello A, Kellner JC, Walker JM, Di Marzo V (2004) Actions of two naturally occurring saturated N-acyldopamines on transient receptor potential vanilloid 1 (TRPV1) channels. Br J Pharm 143:251–256CrossRefGoogle Scholar
  15. Fernando PH, Sakakibara Y, Nakatsu S, Suiko M, Han JR, Liu MC (1993) Isolation and characterization of a novel microsomal membrane-bound phenol sulfotransferase from bovine liver. Biochem Mol Biol Int 30(3):433–441PubMedGoogle Scholar
  16. Ferreira S, Lomaglio T, Avelino A, Cruz F, Oliveira C, Cunha R, Kofalvi A (2009) N-acyldopamines control striatal input terminals via novel ligand-gated cation channels. Neuropharmacology 56:676–683CrossRefPubMedGoogle Scholar
  17. Gaddis B, Avramova LV, Chmielewski J (2007) Inhibitors of anthrax lethal factor. Bioorg Med Chem Lett 17:4575–4578CrossRefPubMedGoogle Scholar
  18. Gaddis B, Rubert Perez C, Chmielewski J (2008) Inhibitors of anthrax lethal factor based upon N-oleoyldopamine. Bioorg Med Chem Lett 18:2467–2470CrossRefPubMedGoogle Scholar
  19. Gonzalez C, Almaraz L, Obeso A, Rigual R (1994) Carotid body chemoreceptors: from natural stimuli to sensory discharges. Physiol Rev 74(4):829–898CrossRefPubMedGoogle Scholar
  20. Hauer D, Schelling G, Gola H, Campolongo P, Morath J, Roozendaal B, Hamuni G, Karabatsiakis A, Atsak P, Vogeser M, Kolassa IT (2013) Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder. PLoS One 8(5):e62741CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hu SS, Bradshaw HB, Benton VM, Chen JS, Huang SM, Minassi A, Bisogno T, Masuda K, Tan B, Roskoski R Jr, Cravatt BF, Di Marzo V, Walker JM (2009) The biosynthesis of N-arachidonyl dopamine (NADA), a putative endocannabinoid and endovanilloid, via conjugation of arachidonic acid with dopamine. Prostaglandins Leukot Essent Fatty Acids 81:291–301CrossRefPubMedPubMedCentralGoogle Scholar
  22. Huang S, Bisogno T, Trevisani M, Al-Hayani A, De Petrocellis L, Fezza F, Tognetto M, Petros T, Krey J, Chu C, Miller J, Davies S, Geppetti P, Walker J, Di Marzo V (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. PNAS 99:8400–8404CrossRefPubMedGoogle Scholar
  23. Ji D, Jang CG, Lee S (2014) A sensitive and accurate quantitative method to determine N-arachidonoyldopamine and N-oleoyldopamine in the mouse striatum using column-switching LC–MS–MS: use of a surrogate matrix to quantify endogenous compounds. Anal Bioanal Chem 406:4491–4499CrossRefPubMedGoogle Scholar
  24. Konieczny J, Przegaliński E, Pokorski M (2009) N-oleoyl-dopamine decreases muscle rigidity induced by reserpine in rats. Int J Immunopathol Pharmacol 22:21–28CrossRefPubMedGoogle Scholar
  25. Marinelli S, Di Marzo V, Berretta N, Matias I, Maccarrone M, Bernardi G, Mercuri NB (2003) Presynaptic facilitation of glutaminergic synapses of the rat substantia nigra by endogenous stimulation of vanilloid receptors. J Neurosci 23:3136–3144CrossRefPubMedGoogle Scholar
  26. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78(1):189–225CrossRefGoogle Scholar
  27. Navarrete CM, Pérez M, Garcıa de Vinuesa A, Collado JA, Fiebich BL, Calzado MA, Muñoz E (2010) Endogenous N-acyl-dopamines induce COX-2 expression in brain endothelial cells by stabilizing mRNA through a p38 dependent pathway. Biochem Pharmacol 79:1805–1814CrossRefPubMedGoogle Scholar
  28. Nguyen MD, Nguyen DH, Yoo JM, Myung PK, Kim MR, Sok DE (2013) Effect of endocannabinoids on soybean lipoxygenase-1 activity. Bioorg Chem 49:24–32CrossRefPubMedGoogle Scholar
  29. Pokorski M, Matysiak Z (1998) Fatty acid acylation of dopamine in the carotid body. Med Hypotheses 50:131–133CrossRefPubMedGoogle Scholar
  30. Pokorski M, Matysiak Z, Marczak M, Ostrowski P, Kapuscinski A, Matuszewska I, Kanska M, Czarnocki Z (2003) Brain uptake of radiolabelled N-oleoyl-dopamine in the rat. Drug Dev Res 60:217–224CrossRefGoogle Scholar
  31. Pokorski M, Zajac D, Kapuscinski A, Matysiak Z, Czarnocki Z (2006) Accumulation of radiolabelled N-oleoyl-dopamine in the rat carotid body. Adv Exp Med Biol 580:173–178CrossRefPubMedGoogle Scholar
  32. Przegalinski E, Filip M, Zajac D, Pokorski M (2006) N-oleoyl-dopamine increases locomotor activity in the rat. Int J Immunopathol Pharmacol 19:897–904CrossRefPubMedGoogle Scholar
  33. Rekawek A, Pokorski M (2011) Influence of 3′-O-methyl-N-oleoyl-dopamine on the hypoxic ventilatory response in the rat. Conference on Advances in Pneumology, Bonn, Germany. Accessed on 13 Mar 2018 (Conference abstract)
  34. Sancho R, Macho A, de La Vega L, Calzado MA, Fiebich BL, Appendino G, Munoz E (2004) Immunosuppressive activity of endovanilloids: N-arachidonoyl-dopamine inhibits activation of the NF-kB, NFAT, and activator protein 1 signaling pathways. J Immunol 172(4):2341–2351CrossRefPubMedGoogle Scholar
  35. Saunders CI, Fassett RG, Geraghty DP (2009) Up-regulation of TRPV1 in mononuclear cells of end-stage kidney disease patients increases susceptibility to N-arachidonoyl-dopamine (NADA)-induced cell death. Biochim Biophys Acta 1792:1019–1026CrossRefPubMedGoogle Scholar
  36. Shirazi M, Izadi M, Amin M, Rezvani ME, Roohbakhsh A, Shamsizadeh A (2014) Involvement of central TRPV1 receptors in pentylenetetrazole and amygdala-induced kindling in male rats. Neurol Sci 35:1235–1241CrossRefPubMedGoogle Scholar
  37. Spicarova D, Palecek J (2009) The role of the TRPV1 endogenous agonist N-oleoyldopamine in modulation of nociceptive signaling at the spinal cord level. J Neurophysiol 102:234–243CrossRefPubMedGoogle Scholar
  38. Spicarova D, Palecek J (2010) Tumor necrosis factor alpha sensitizes spinal cord TRPV1 receptors to the endogenous agonist N-oleoyldopamine. J Neuroinflamm 7:49CrossRefGoogle Scholar
  39. Szolcsanyi J, Sandora Z, Petho G, Varga A, Bolcskei K, Almasi R, Riedl Z, Hajos G, Czeh G (2004) Direct evidence for activation and desensitization of the capsaicin receptor by N-oleoyldopamine on TRPV1-transfected cell, line in gene deleted mice and in the rat. Neurosci Lett 361:155–158CrossRefPubMedGoogle Scholar
  40. Visnyei K, Onodera H, Damoiseaux R, Saigusa K, Petrosyan S, De Vries D, Ferrari D, Saxe J, Panosyan EH, Masterman-Smith M, Mottahedeh J, Bradley KA, Huang J, Sabatti C, Nakano I, Kornblum HI (2011) A molecular screening approach to identify and characterize inhibitors of glioblastoma stem cells. Mol Cancer Ther 10(10):1818–1828CrossRefPubMedPubMedCentralGoogle Scholar
  41. Walpole CS, Wrigglesworth R, Bevan S, Campbell EA, Dray A, James IF, Perkins MN, Reid DJ, Winter J (1993a) Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 1. The aromatic ‘A-region’. J Med Chem 36(16):2362–2372CrossRefPubMedGoogle Scholar
  42. Walpole CS, Wrigglesworth R, Bevan S, Campbell EA, Dray A, James IF, Masdin KJ, Perkins MN, Winter J (1993b) Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 2. The amide bond ‘B-region’. J Med Chem 36(16):2373–2380CrossRefPubMedGoogle Scholar
  43. Zajac D (2009) Bioproperties of N-oleoyl-dopamine, a new lipid derivative of dopamine, with special attention to its influence on respiration in rats. PhD thesis, Mossakowski Medical Research Centre, Warsaw, Poland (in Polish)Google Scholar
  44. Zajac D, Matysiak Z, Czarnocki Z, Pokorski M (2006) Membrane association of N-oleoyl-dopamine in the rat brain. J Physiol Pharmacol 57(Suppl 4):403–408PubMedGoogle Scholar
  45. Zajac D, Roszkowski P, Czarnocki Z, Pokorski M (2010) Influence of TRPV1 (vanilloid) blockade on the respiratory response to hypoxia after N-oleoyl-dopamine in anesthetized rats. Conference on Advances in Pneumology, Warsaw, Poland. Accessed on 13 Mar 2018 (Conference abstract)
  46. Zajac D, Spolnik G, Roszkowski P, Danikiewicz W, Czarnocki Z, Pokorski M (2014) Metabolism of N-acylated-dopamine. PLoS One 9(1):e85259CrossRefPubMedPubMedCentralGoogle Scholar
  47. Zajac D, Stasinska A, Pokorski M (2018) Oleic derivatives of dopamine and respiration. Adv Exp Med Biol 1023:37–46CrossRefPubMedGoogle Scholar
  48. Zhong B, Wang D (2008) N-oleoyl-dopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1. Am J Physiol Heart Circ Physiol 295:H728–H735CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculty of PhysiotherapyOpole Medical SchoolOpolePoland
  2. 2.Laboratory of Respiration PhysiologyMossakowski Medical Research Centre PASWarsawPoland

Personalised recommendations