Generic placeholder image

Current Bioactive Compounds

Editor-in-Chief

ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

Review Article

Old Strategies and New Perspectives in Modulating the Endocannabinoid System

Author(s): Brizzi Antonella and Pessina Federica*

Volume 15, Issue 2, 2019

Page: [159 - 173] Pages: 15

DOI: 10.2174/1573407214666180627144214

Price: $65

Open Access Journals Promotions 2
Abstract

Endocannabinoid System (ES) has gained over the years a leading position in scientific research thanks to its involvement in numerous patho/physiological conditions. Accordingly, its main components, such as receptors, enzymes and mediators, have become important drug targets for the management of diseases where it is dysregulated. Within the manuscript, several classes of cannabinergic ligands are examined, emphasizing molecules coming from the natural world, unique source of active compounds. Firstly, the endogenous lipid ES modulators are described, starting from the major endocannabinoids to the plethora of endocannabinoid congeners. Afterwards, Cannabis-derived cannabinoids, namely well-known phytocannabinoids and new constituents from different varieties of Cannabis, are reviewed also mentioning the huge effort of pharmaceutical research in obtaining synthetic analogues. Finally, an overview of peptides and miscellaneous natural products points out new opportunities to modulate ES, offering an enormous chemical heterogeneity. Accordingly, hemopressin and related peptides, plant-derived alkylamides, terpenoid derivatives, neolignans and examples from the marine world can provide interesting hints and original ideas to develop new cannabinergic compounds.

Keywords: Endocannabinoid, cannabinergic, phytocannabinoids, alkylamides, terpenoids, neolignans, indoles, marine derivatives.

Graphical Abstract
[1]
Gaoni, Y.; Mechoulam, R. Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. J. Am. Chem. Soc., 1964, 86, 1646-1647.
[2]
Devane, W.A.; Dysarz, F.A., III; Johnson, M.R.; Melvin, L.S.; Howlett, A.C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol., 1988, 34(5), 605-613.
[3]
Matsuda, L.A.; Lolait, S.J.; Brownstein, M.J.; Young, A.C.; Bonner, T.I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 1990, 346(6284), 561-564.
[4]
Munro, S.; Thomas, K.L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature, 1993, 365(6441), 61-65.
[5]
Devane, W.A.; Hanus, L.; Breuer, A.; Pertwee, R.G.; Stevenson, L.A.; Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger, A.; Mechoulam, R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 1992, 258(5090), 1946-1949.
[6]
Mechoulam, R.; Ben-Shabat, S.; Hanus, L.; Ligumsky, M.; Kaminski, N.E.; Schatz, A.R.; Gopher, A.; Almog, S.; Martin, B.R.; Compton, D.R.; Pertwee, R.G.; Griffin, G.; Bayewitch, M.; Barg, J.; Vogel, Z. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol., 1995, 50(1), 83-90.
[7]
Cravatt, B.F.; Giang, D.K.; Mayfield, S.P.; Boger, D.L.; Lerner, R.A.; Gilula, N.B. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature, 1996, 384(6604), 83-87.
[8]
Dinh, T.P.; Kathuria, S.; Piomelli, D. RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. Mol. Pharmacol., 2004, 66(5), 1260-1264.
[9]
Deutsch, D.G.; Chin, S.A. Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem. Pharmacol., 1993, 46(5), 791-796.
[10]
Di Marzo, V.; Fontana, A.; Cadas, H.; Schinelli, S.; Cimino, G.; Schwartz, J-C.; Piomelli, D. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature, 1994, 372(6507), 686-691.
[11]
Zygmunt, P.M.; Petersson, J.; Andersson, D.A.; Chuang, H.; Sørgård, M.; Di Marzo, V.; Julius, D.; Högestätt, E.D. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature, 1999, 400(6743), 452-457.
[12]
Smart, D.; Gunthorpe, M.J.; Jerman, J.C.; Nasir, S.; Gray, J.; Muir, A.I.; Chambers, J.K.; Randall, A.D.; Davis, J.B. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br. J. Pharmacol., 2000, 129(2), 227-230.
[13]
Price, M.R.; Baillie, G.L.; Thomas, A.; Stevenson, L.A.; Easson, M.; Goodwin, R.; McLean, A.; McIntosh, L.; Goodwin, G.; Walker, G.; Westwood, P.; Marrs, J.; Thomson, F.; Cowley, P.; Christopoulos, A.; Pertwee, R.G.; Ross, R.A. Allosteric modulation of the cannabinoid CB1 receptor. Mol. Pharmacol., 2005, 68(5), 1484-1495.
[14]
Pertwee, R.G.; Howlett, A.C.; Abood, M.E.; Alexander, S.P.H.; Di Marzo, V.; Elphick, M.R.; Greasley, P.J.; Hansen, H.S.; Kunos, G.; Mackie, K.; Mechoulam, R.; Ross, R.A. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol. Rev., 2010, 62(4), 588-631.
[15]
Mackie, K.; Devane, W.A.; Hille, B. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol. Pharmacol., 1993, 44(3), 498-503.
[16]
Burkey, T.H.; Quock, R.M.; Consroe, P.; Ehlert, F.J.; Hosohata, Y.; Roeske, W.R.; Yamamura, H.I. Relative efficacies of cannabinoid CB1 receptor agonists in the mouse brain. Eur. J. Pharmacol., 1997, 336(2-3), 295-298.
[17]
Glass, M.; Northup, J.K. Agonist selective regulation of G proteins by cannabinoid CB(1) and CB(2) receptors. Mol. Pharmacol., 1999, 56(6), 1362-1369.
[18]
Twitchell, W.; Brown, S.; Mackie, K. Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J. Neurophysiol., 1997, 78(1), 43-50.
[19]
Morisset, V.; Urban, L. Cannabinoid-induced presynaptic inhibition of glutamatergic EPSCs in substantia gelatinosa neurons of the rat spinal cord. J. Neurophysiol., 2001, 86(1), 40-48.
[20]
Svízenská, I.; Dubový, P.; Sulcová, A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures--a short review. Pharmacol. Biochem. Behav., 2008, 90(4), 501-511.
[21]
Savinainen, J.R.; Järvinen, T.; Laine, K.; Laitinen, J.T. Despite substantial degradation, 2-arachidonoylglycerol is a potent full efficacy agonist mediating CB(1) receptor-dependent G-protein activation in rat cerebellar membranes. Br. J. Pharmacol., 2001, 134(3), 664-672.
[22]
Gonsiorek, W.; Lunn, C.; Fan, X.; Narula, S.; Lundell, D.; Hipkin, R.W. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol. Pharmacol., 2000, 57(5), 1045-1050.
[23]
Sugiura, T.; Kondo, S.; Sukagawa, A.; Nakane, S.; Shinoda, A.; Itoh, K.; Yamashita, A.; Waku, K. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun., 1995, 215(1), 89-97.
[24]
Sugiura, T.; Kishimoto, S.; Oka, S.; Gokoh, M. Biochemistry, pharmacology and physiology of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Prog. Lipid Res., 2006, 45(5), 405-446.
[25]
Cristino, L.; de Petrocellis, L.; Pryce, G.; Baker, D.; Guglielmotti, V.; Di Marzo, V. Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience, 2006, 139(4), 1405-1415.
[26]
Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P.J. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol., 2007, 152(7), 1092-1101.
[27]
Roberts, L.A.; Christie, M.J.; Connor, M. Anandamide is a partial agonist at native vanilloid receptors in acutely isolated mouse trigeminal sensory neurons. Br. J. Pharmacol., 2002, 137(4), 421-428.
[28]
Sharir, H.; Console-Bram, L.; Mundy, C.; Popoff, S.N.; Kapur, A.; Abood, M.E. The endocannabinoids anandamide and virodhamine modulate the activity of the candidate cannabinoid receptor GPR55. J. Neuroimmune Pharmacol., 2012, 7(4), 856-865.
[29]
Hanus, L.; Abu-Lafi, S.; Fride, E.; Breuer, A.; Vogel, Z.; Shalev, D.E.; Kustanovich, I.; Mechoulam, R. 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl. Acad. Sci. USA, 2001, 98(7), 3662-3665.
[30]
Porter, A.C.; Sauer, J.M.; Knierman, M.D.; Becker, G.W.; Berna, M.J.; Bao, J.; Nomikos, G.G.; Carter, P.; Bymaster, F.P.; Leese, A.B.; Felder, C.C. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J. Pharmacol. Exp. Ther., 2002, 301(3), 1020-1024.
[31]
Bisogno, T.; Melck, D. Bobrov MYu; Gretskaya, N.M.; Bezuglov, V.V.; De Petrocellis, L.; Di Marzo, V. N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem. J., 2000, 351(Pt 3), 817-824.
[32]
Steffens, M.; Zentner, J.; Honegger, J.; Feuerstein, T.J. Binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical CB1 receptor. Biochem. Pharmacol., 2005, 69(1), 169-178.
[33]
Shoemaker, J.L.; Joseph, B.K.; Ruckle, M.B.; Mayeux, P.R.; Prather, P.L. The endocannabinoid noladin ether acts as a full agonist at human CB2 cannabinoid receptors. J. Pharmacol. Exp. Ther., 2005, 314(2), 868-875.
[34]
Huang, S.M.; Bisogno, T.; Trevisani, M.; Al-Hayani, A.; De Petrocellis, L.; Fezza, F.; Tognetto, M.; Petros, T.J.; Krey, J.F.; Chu, C.J.; Miller, J.D.; Davies, S.N.; Geppetti, P.; Walker, J.M.; Di Marzo, V. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc. Natl. Acad. Sci. USA, 2002, 99(12), 8400-8405.
[35]
Fawley, J.A.; Hofmann, M.E.; Andresen, M.C. Cannabinoid 1 and transient receptor potential vanilloid 1 receptors discretely modulate evoked glutamate separately from spontaneous glutamate transmission. J. Neurosci., 2014, 34(24), 8324-8332.
[36]
Brown, I.; Cascio, M.G.; Rotondo, D.; Pertwee, R.G.; Heys, S.D.; Wahle, K.W.J. Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators. Prog. Lipid Res., 2013, 52(1), 80-109.
[37]
Gabrielsson, L.; Mattsson, S.; Fowler, C.J. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Br. J. Clin. Pharmacol., 2016, 82(4), 932-942.
[38]
Ahmad, A.; Crupi, R.; Impellizzeri, D.; Campolo, M.; Marino, A.; Esposito, E.; Cuzzocrea, S. Administration of palmitoylethanolamide (PEA) protects the neurovascular unit and reduces secondary injury after traumatic brain injury in mice. Brain Behav. Immun., 2012, 26(8), 1310-1321.
[39]
Petrosino, S.; Cristino, L.; Karsak, M.; Gaffal, E.; Ueda, N.; Tüting, T.; Bisogno, T.; De Filippis, D.; D’Amico, A.; Saturnino, C.; Orlando, P.; Zimmer, A.; Iuvone, T.; Di Marzo, V. Protective role of palmitoylethanolamide in contact allergic dermatitis. Allergy, 2010, 65(6), 698-711.
[40]
Borrelli, F.; Romano, B.; Petrosino, S.; Pagano, E.; Capasso, R.; Coppola, D.; Battista, G.; Orlando, P.; Di Marzo, V.; Izzo, A.A. Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inflammatory agent. Br. J. Pharmacol., 2015, 172(1), 142-158.
[41]
Pessina, F.; Capasso, R.; Borrelli, F.; Aveta, T.; Buono, L.; Valacchi, G.; Fiorenzani, P.; Di Marzo, V.; Orlando, P.; Izzo, A.A. Protective effect of palmitoylethanolamide in a rat model of cystitis. J. Urol., 2015, 193(4), 1401-1408.
[42]
De Petrocellis, L.; Di Marzo, V. An introduction to the endocannabinoid system: from the early to the latest concepts. Best Pract. Res. Clin. Endocrinol. Metab., 2009, 23(1), 1-15.
[43]
Grotenhermen, F.; Russo, E. Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential, 1st ed; Haworth Press, Inc.: New York, 2002.
[44]
De Petrocellis, L.; Ligresti, A.; Moriello, A.S.; Allarà, M.; Bisogno, T.; Petrosino, S.; Stott, C.G.; Di Marzo, V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol., 2011, 163(7), 1479-1494.
[45]
De Petrocellis, L.; Orlando, P.; Moriello, A.S.; Aviello, G.; Stott, C.; Izzo, A.A.; Di Marzo, V. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol. (Oxf.), 2012, 204(2), 255-266.
[46]
Pertwee, R.G. Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr. Med. Chem., 2010, 17(14), 1360-1381.
[47]
Silverberg, L.J. Synthesis of Cannabinoids. U. S. Patent 7,186,850, March 6 2007.
[48]
Hippalgaonkar, K.; Gul, W.; ElSohly, M.A.; Repka, M.A.; Majumdar, S. Enhanced solubility, stability, and transcorneal permeability of δ-8-tetrahydrocannabinol in the presence of cyclodextrins. AAPS PharmSciTech, 2011, 12(2), 723-731.
[49]
Showalter, V.M.; Compton, D.R.; Martin, B.R.; Abood, M.E. Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of cannabinoid receptor subtype selective ligands. J. Pharmacol. Exp. Ther., 1996, 278(3), 989-999.
[50]
Thomas, A.; Baillie, G.L.; Phillips, A.M.; Razdan, R.K.; Ross, R.A.; Pertwee, R.G. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br. J. Pharmacol., 2007, 150(5), 613-623.
[51]
McPartland, J.M.; Duncan, M.; Di Marzo, V.; Pertwee, R.G. Are cannabidiol and (Δ9)-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br. J. Pharmacol., 2015, 172(3), 737-753.
[52]
Ibeas Bih, C.; Chen, T.; Nunn, A.V.W.; Bazelot, M.; Dallas, M.; Whalley, B.J. Molecular Targets of Cannabidiol in Neurological Disorders. Neurotherapeutics, 2015, 12(4), 699-730.
[53]
Friedman, D.; Devinsky, O. Cannabinoids in the treatment of epilepsy. N. Engl. J. Med., 2015, 373(11), 1048-1058.
[54]
Riedel, G.; Fadda, P.; McKillop-Smith, S.; Pertwee, R.G.; Platt, B.; Robinson, L. Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br. J. Pharmacol., 2009, 156(7), 1154-1166.
[55]
Bolognini, D.; Costa, B.; Maione, S.; Comelli, F.; Marini, P.; Di Marzo, V.; Parolaro, D.; Ross, R.A.; Gauson, L.A.; Cascio, M.G.; Pertwee, R.G. The plant cannabinoid Delta9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice. Br. J. Pharmacol., 2010, 160(3), 677-687.
[56]
Romano, B.; Pagano, E.; Orlando, P.; Capasso, R.; Cascio, M.G.; Pertwee, R.; Marzo, V.D.; Izzo, A.A.; Borrelli, F. Pure Δ9- tetrahydrocannabivarin and a Cannabis sativa extract with high content in Δ9-tetrahydrocannabivarin inhibit nitrite production in murine peritoneal macrophages. Pharmacol. Res., 2016, 113(Pt A), 199-208.
[57]
Appendino, G.; Giana, A.; Gibbons, S.; Maffeic, M.; Gnavic, G.; Grassi, G.; Sterner, O. A Polar Cannabinoid from Cannabis sativa var. Carma. Nat. Prod. Communic., 2008, 3, 1977-1980.
[58]
Appendino, G.; Gibbons, S.; Giana, A.; Pagani, A.; Grassi, G.; Stavri, M.; Smith, E.; Rahman, M.M. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J. Nat. Prod., 2008, 71(8), 1427-1430.
[59]
Radwan, M.M.; Elsohly, M.A.; Slade, D.; Ahmed, S.A.; Khan, I.A.; Ross, S.A. Biologically active cannabinoids from high-potency Cannabis sativa. J. Nat. Prod., 2009, 72(5), 906-911.
[60]
Taglialatela-Scafati, O.; Pagani, A.; Scala, F.; De Petrocellis, L.; Di Marzo, V.; Grassi, G.; Giovanni, G.; Appendino, G. Cannabimovone, a Cannabinoid with a Rearranged Terpenoid Skeleton from Hemp. Eur. J. Org. Chem., 2010, 11, 2067-2072.
[61]
Radwan, M.M.; ElSohly, M.A.; El-Alfy, A.T.; Ahmed, S.A.; Slade, D.; Husni, A.S.; Manly, S.P.; Wilson, L.; Seale, S.; Cutler, S.J.; Ross, S.A. Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa. J. Nat. Prod., 2015, 78(6), 1271-1276.
[62]
Howlett, A.C.; Barth, F.; Bonner, T.I.; Cabral, G.; Casellas, P.; Devane, W.A.; Felder, C.C.; Herkenham, M.; Mackie, K.; Martin, B.R.; Mechoulam, R.; Pertwee, R.G. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev., 2002, 54(2), 161-202.
[63]
Bow, E.W.; Rimoldi, J.M. The Structure-Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation. Perspect. Medicin. Chem., 2016, 8, 17-39.
[64]
Rioli, V.; Gozzo, F.C.; Heimann, A.S.; Linardi, A.; Krieger, J.E.; Shida, C.S.; Almeida, P.C.; Hyslop, S.; Eberlin, M.N.; Ferro, E.S. Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme. J. Biol. Chem., 2003, 278(10), 8547-8555.
[65]
Dale, C.S. Pagano, Rde.L.; Rioli, V.; Hyslop, S.; Giorgi, R.; Ferro, E.S. Antinociceptive action of hemopressin in experimental hyperalgesia. Peptides, 2005, 26(3), 431-436.
[66]
Heimann, A.S.; Gomes, I.; Dale, C.S.; Pagano, R.L.; Gupta, A.; de Souza, L.L.; Luchessi, A.D.; Castro, L.M.; Giorgi, R.; Rioli, V.; Ferro, E.S.; Devi, L.A. Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc. Natl. Acad. Sci. USA, 2007, 104(51), 20588-20593.
[67]
Macedonio, G.; Stefanucci, A.; Maccallini, C.; Mirzaie, S.; Novellino, E.; Mollica, A. Hemopressin Peptides as Modulators of the Endocannabinoid System and their Potential Applications as Therapeutic Tools. Protein Pept. Lett., 2016, 23(12), 1045-1051.
[68]
Dodd, G.T.; Mancini, G.; Lutz, B.; Luckman, S.M. The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice. J. Neurosci., 2010, 30(21), 7369-7376.
[69]
Ferrante, C.; Recinella, L.; Leone, S.; Chiavaroli, A.; Di Nisio, C.; Martinotti, S.; Mollica, A.; Macedonio, G.; Stefanucci, A.; Dvorácskó, S.; Tömböly, C.; De Petrocellis, L.; Vacca, M.; Brunetti, L.; Orlando, G. Anorexigenic effects induced by RVD-hemopressin(α) administration. Pharmacol. Rep., 2017, 69(6), 1402-1407.
[70]
Toniolo, E.F.; Maique, E.T.; Ferreira, W.A., Jr; Heimann, A.S.; Ferro, E.S.; Ramos-Ortolaza, D.L.; Miller, L.; Devi, L.A.; Dale, C.S. Hemopressin, an inverse agonist of cannabinoid receptors, inhibits neuropathic pain in rats. Peptides, 2014, 56, 125-131.
[71]
Scrima, M.; Di Marino, S.; Grimaldi, M.; Mastrogiacomo, A.; Novellino, E.; Bifulco, M.; D’Ursi, A.M. Binding of the hemopressin peptide to the cannabinoid CB1 receptor: structural insights. Biochemistry, 2010, 49(49), 10449-10457.
[72]
Bomar, M.G.; Galande, A.K. Modulation of the cannabinoid receptors by hemopressin peptides. Life Sci., 2013, 92(8-9), 520-524.
[73]
Gomes, I.; Grushko, J.S.; Golebiewska, U.; Hoogendoorn, S.; Gupta, A.; Heimann, A.S.; Ferro, E.S.; Scarlata, S.; Fricker, L.D.; Devi, L.A. Novel endogenous peptide agonists of cannabinoid receptors. FASEB J., 2009, 23(9), 3020-3029.
[74]
Bomar, M.G.; Samuelsson, S.J.; Kibler, P.; Kodukula, K.; Galande, A.K. Hemopressin forms self-assembled fibrillar nanostructures under physiologically relevant conditions. Biomacromolecules, 2012, 13(3), 579-583.
[75]
Leone, S.; Recinella, L.; Chiavaroli, A.; Martinotti, S.; Ferrante, C.; Mollica, A.; Macedonio, G.; Stefanucci, A.; Dvorácskó, S.; Tömböly, C.; De Petrocellis, L.; Vacca, M.; Brunetti, L.; Orlando, G. Emotional disorders induced by Hemopressin and RVD-hemopressin(α) administration in rats. Pharmacol. Rep., 2017, 69(6), 1247-1253.
[76]
Fogaça, M.V.; Sonego, A.B.; Rioli, V.; Gozzo, F.C.; Dale, C.S.; Ferro, E.S.; Guimarães, F.S. Anxiogenic-like effects induced by hemopressin in rats. Pharmacol. Biochem. Behav., 2015, 129, 7-13.
[77]
Petrucci, V.; Chicca, A.; Glasmacher, S.; Paloczi, J.; Cao, Z.; Pacher, P.; Gertsch, J. Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage. Sci. Rep., 2017, 7(1), 9560.
[78]
Rios, M.Y. Natural Alkamides: Pharmacology, Chemistry and Distribution. In: ; Vallisuta, O., Olimat, S. M., Drug Discovery; IntechOpen: London, 2012; pp. 1-7-144.
[79]
Raduner, S.; Majewska, A.; Chen, J-Z.; Xie, X-Q.; Hamon, J.; Faller, B.; Altmann, K-H.; Gertsch, J. Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects. J. Biol. Chem., 2006, 281(20), 14192-14206.
[80]
Ruiu, S.; Anzani, N.; Orrù, A.; Floris, C.; Caboni, P.; Maccioni, E.; Distinto, S.; Alcaro, S.; Cottiglia, F. N-Alkyl dien- and trienamides from the roots of Otanthus maritimus with binding affinity for opioid and cannabinoid receptors. Bioorg. Med. Chem., 2013, 21(22), 7074-7082.
[81]
Gertsch, J. Immunomodulatory lipids in plants: plant fatty acid amides and the human endocannabinoid system. Planta Med., 2008, 74(6), 638-650.
[82]
Matovic, N.; Matthias, A.; Gertsch, J.; Raduner, S.; Bone, K.M.; Lehmann, R.P.; Devoss, J.J. Stereoselective synthesis, natural occurrence and CB(2) receptor binding affinities of alkylamides from herbal medicines such as Echinacea sp. Org. Biomol. Chem., 2007, 5(1), 169-174.
[83]
Nicolussi, S.; Viveros-Paredes, J.M.; Gachet, M.S.; Rau, M.; Flores-Soto, M.E.; Blunder, M.; Gertsch, J. Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice. Pharmacol. Res., 2014, 80, 52-65.
[84]
Yu, S.; Levi, L.; Casadesus, G.; Kunos, G.; Noy, N. Fatty acid-binding protein 5 (FABP5) regulates cognitive function both by decreasing anandamide levels and by activating the nuclear receptor PPARβ/δ in the brain. J. Biol. Chem., 2014, 289, 12748-12758.
[85]
Nicolussi, S.; Chicca, A.; Rau, M.; Rihs, S.; Soeberdt, M.; Abels, C.; Gertsch, J. Correlating FAAH and anandamide cellular uptake inhibition using N-alkylcarbamate inhibitors: from ultrapotent to hyperpotent. Biochem. Pharmacol., 2014, 92(4), 669-689.
[86]
Sugai, E.; Morimitsu, Y.; Kubota, K. Quantitative analysis of sanshool compounds in Japanese pepper (Xanthoxylum piperitum DC.) and their pungent characteristics. Biosci. Biotechnol. Biochem., 2005, 69(10), 1958-1962.
[87]
Sugai, E.; Morimitsu, Y.; Iwasaki, Y.; Morita, A.; Watanabe, T.; Kubota, K. Pungent qualities of sanshool-related compounds evaluated by a sensory test and activation of rat TRPV1. Biosci. Biotechnol. Biochem., 2005, 69(10), 1951-1957.
[88]
Dossou, K.S.S.; Devkota, K.P.; Morton, C.; Egan, J.M.; Lu, G.; Beutler, J.A.; Moaddel, R. Identification of CB1/CB2 ligands from Zanthoxylum bungeanum. J. Nat. Prod., 2013, 76(11), 2060-2064.
[89]
Gertsch, J.; Leonti, M.; Raduner, S.; Racz, I.; Chen, J.Z.; Xie, X.Q.; Altmann, K.H.; Karsak, M.; Zimmer, A. Beta-caryophyllene is a dietary cannabinoid. Proc. Natl. Acad. Sci. USA, 2008, 105(26), 9099-9104.
[90]
Cho, J.Y.; Chang, H.J.; Lee, S.K.; Kim, H.J.; Hwang, J.K.; Chun, H.S. Amelioration of dextran sulfate sodium-induced colitis in mice by oral administration of beta-caryophyllene, a sesquiterpene. Life Sci., 2007, 80(10), 932-939.
[91]
Bento, A.F.; Marcon, R.; Dutra, R.C.; Claudino, R.F.; Cola, M.; Leite, D.F.; Calixto, J.B. β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway. Am. J. Pathol., 2011, 178(3), 1153-1166.
[92]
Katsuyama, S.; Mizoguchi, H.; Kuwahata, H.; Komatsu, T.; Nagaoka, K.; Nakamura, H.; Bagetta, G.; Sakurada, T.; Sakurada, S. Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception. Eur. J. Pain, 2013, 17(5), 664-675.
[93]
Guo, K.; Mou, X.; Huang, J.; Xiong, N.; Li, H. Trans-caryophyllene suppresses hypoxia-induced neuroinflammatory responses by inhibiting NF-κB activation in microglia. J. Mol. Neurosci., 2014, 54(1), 41-48.
[94]
Cheng, Y.; Dong, Z.; Liu, S. β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway. Pharmacology, 2014, 94(1-2), 1-12.
[95]
Chicca, A.; Caprioglio, D.; Minassi, A.; Petrucci, V.; Appendino, G.; Taglialatela-Scafati, O.; Gertsch, J. Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system. ACS Chem. Biol., 2014, 9(7), 1499-1507.
[96]
King, A.R.; Dotsey, E.Y.; Lodola, A.; Jung, K.M.; Ghomian, A.; Qiu, Y.; Fu, J.; Mor, M.; Piomelli, D. Discovery of potent and reversible monoacylglycerol lipase inhibitors. Chem. Biol., 2009, 16(10), 1045-1052.
[97]
Yang, L.; Li, Y.; Ren, J.; Zhu, C.; Fu, J.; Lin, D.; Qiu, Y. Celastrol attenuates inflammatory and neuropathic pain mediated by cannabinoid receptor type 2. Int. J. Mol. Sci., 2014, 15(8), 13637-13648.
[98]
Liu, J.; Lee, J.; Salazar Hernandez, M.A.; Mazitschek, R.; Ozcan, U. Treatment of obesity with celastrol. Cell, 2015, 161(5), 999-1011.
[99]
Blankman, J.L.; Simon, G.M.; Cravatt, B.F. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem. Biol., 2007, 14(12), 1347-1356.
[100]
Ueda, N.; Yamanaka, K.; Yamamoto, S. Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance. J. Biol. Chem., 2001, 276(38), 35552-35557.
[101]
Vázquez, L.H.; Palazon, J.; Navarro-Ocaña, A. The Pentacyclic Triterpenes alpha, beta-amyrins: A Review of Sources and Biological Activities.In: Rao V. Ed.;Phytochemicals – A Global Perspective of Their Role in Nutrition and Health; InTechOpen; Newyork, 2012, pp. 487-502.
[102]
da Silva, K.A.; Paszcuk, A.F.; Passos, G.F.; Silva, E.S.; Bento, A.F.; Meotti, F.C.; Calixto, J.B. Activation of cannabinoid receptors by the pentacyclic triterpene α,β-amyrin inhibits inflammatory and neuropathic persistent pain in mice. Pain, 2011, 152(8), 1872-1887.
[103]
Chicca, A.; Marazzi, J.; Gertsch, J. The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting cannabinoid receptors. Br. J. Pharmacol., 2012, 167(8), 1596-1608.
[104]
Yang, R.; Yuan, B-C.; Ma, Y-S.; Zhou, S.; Liu, Y. The anti-inflammatory activity of licorice, a widely used Chinese herb. Pharm. Biol., 2017, 55(1), 5-18.
[105]
Park, M.; Lee, J-H.; Choi, J.K.; Hong, Y.D.; Bae, I-H.; Lim, K-M.; Park, Y-H.; Ha, H. 18β-glycyrrhetinic acid attenuates anandamide-induced adiposity and high-fat diet induced obesity. Mol. Nutr. Food Res., 2014, 58(7), 1436-1446.
[106]
Lee, Y-J.; Lee, Y.M.; Lee, C-K.; Jung, J.K.; Han, S.B.; Hong, J.T. Therapeutic applications of compounds in the Magnolia family. Pharmacol. Ther., 2011, 130(2), 157-176.
[107]
Rempel, V.; Fuchs, A.; Hinz, S.; Karcz, T.; Lehr, M.; Koetter, U.; Müller, C.E. Magnolia Extract, Magnolol, and Metabolites: Activation of Cannabinoid CB2 Receptors and Blockade of the Related GPR55. ACS Med. Chem. Lett., 2012, 4(1), 41-45.
[108]
Fuchs, A.; Rempel, V.; Müller, C.E. The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists. PLoS One, 2013, 8(10), e77739.
[109]
Coppola, M.; Mondola, R. Potential use of Magnolia officinalis bark polyphenols in the treatment of cannabis dependence. Med. Hypotheses, 2014, 83(6), 673-676.
[110]
Schuehly, W.; Paredes, J.M.V.; Kleyer, J.; Huefner, A.; Anavi-Goffer, S.; Raduner, S.; Altmann, K-H.; Gertsch, J. Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB(2) receptor inverse agonists. Chem. Biol., 2011, 18(8), 1053-1064.
[111]
Chicca, A.; Gachet, M.S.; Petrucci, V.; Schuehly, W.; Charles, R-P.; Gertsch, J. 4′-O-methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation. J. Neuroinflammation, 2015, 12, 89.
[112]
Lambert, D.M.; Fowler, C.J. The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications. J. Med. Chem., 2005, 48(16), 5059-5087.
[113]
Hussain, H.; Hussain, J.; Al-Harrasi, A.; Green, I.R. Chemistry and biology of the genus Voacanga. Pharm. Biol., 2012, 50(9), 1183-1193.
[114]
Kitajima, M.; Iwai, M.; Kikura-Hanajiri, R.; Goda, Y.; Iida, M.; Yabushita, H.; Takayama, H. Discovery of indole alkaloids with cannabinoid CB1 receptor antagonistic activity. Bioorg. Med. Chem. Lett., 2011, 21(7), 1962-1964.
[115]
Gerwick, W.H.; Moore, B.S. Lessons from the past and charting the future of marine natural products drug discovery and chemical biology. Chem. Biol., 2012, 19(1), 85-98.
[116]
Han, B.; McPhail, K.L.; Ligresti, A.; Di Marzo, V.; Gerwick, W.H. Semiplenamides A-G, fatty acid amides from a Papua New Guinea collection of the marine cyanobacterium Lyngbya semiplena. J. Nat. Prod., 2003, 66(10), 1364-1368.
[117]
Montaser, R.; Paul, V.J.; Luesch, H. Marine cyanobacterial fatty acid amides acting on cannabinoid receptors. ChemBioChem, 2012, 13(18), 2676-2681.
[118]
Mevers, E.; Matainaho, T.; Allarà’, M.; Di Marzo, V.; Gerwick, W.H.; Mooreamide, A. Mooreamide A: a cannabinomimetic lipid from the marine cyanobacterium Moorea bouillonii. Lipids, 2014, 49(11), 1127-1132.
[119]
Pereira, A.; Pfeifer, T.A.; Grigliatti, T.A.; Andersen, R.J. Functional cell-based screening and saturation transfer double-difference NMR have identified haplosamate A as a cannabinoid receptor agonist. ACS Chem. Biol., 2009, 4(2), 139-144.
[120]
Chianese, G.; Fattorusso, E.; Taglialatela-Scafati, O.; Bavestrello, G.; Calcinai, B.; Dien, H.A.; Ligresti, A.; Di Marzo, V. Desulfohaplosamate, a new phosphate-containing steroid from Dasychalina sp., is a selective cannabinoid CB2 receptor ligand. Steroids, 2011, 76(10-11), 998-1002.
[121]
Fujita, M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh, Y.; Van Soest, R.W.M.; Heubes, M.; Faulkner, D.J.; Fusetani, N. Isolation and structure elucidation of two phosphorylated sterol sulfates, MT1-MMP inhibitors from a marine sponge Cribrochalina sp.: Revision of the structures of haplosamates A and B. Tetrahedron, 2001, 57, 3885-3890.
[122]
Rigano, D.; Formisano, C.; Taglialatela-Scafati, O. Marine Metabolites Modulating CB Receptors and TRP Channels. Planta Med., 2016, 82(9-10), 761-766.
[123]
Harms, H.; Rempel, V.; Kehraus, S.; Kaiser, M.; Hufendiek, P.; Müller, C.E.; König, G.M. Indoloditerpenes from a marine-derived fungal strain of Dichotomomyces cejpii with antagonistic activity at GPR18 and cannabinoid receptors. J. Nat. Prod., 2014, 77(3), 673-677.
[124]
Elsebai, M.F.; Rempel, V.; Schnakenburg, G.; Kehraus, S.; Müller, C.E.; König, G.M. Identification of a Potent and Selective Cannabinoid CB1 Receptor Antagonist from Auxarthron reticulatum. ACS Med. Chem. Lett., 2011, 2(11), 866-869.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy