Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 391, Issue 4, pp 435–444 | Cite as

Novel derivatives of 1,2,3-triazole, cannabinoid-1 receptor ligands modulate gastrointestinal motility in mice

  • Agata Szymaszkiewicz
  • Marta Zielinska
  • Kun Li
  • Mani Ramanathan
  • Safiul Alam
  • Duen-Ren Hou
  • Jakub Fichna
  • Martin Storr
Original Article
  • 105 Downloads

Abstract

Cannabinoid-1 (CB1) receptors are broadly distributed in the central and peripheral nervous systems; among others, they are located in the enteric nervous system. In the gastrointestinal (GI) system, they participate in regulation of intestinal motility or ion transport. The aim of our study was to assess the effect of 1,2,3-triazole derivatives (compound 1: 2-[4,5-bis(2,4-dichlorophenyl)-2H-1,2,3-triazol-2-yl]-N-(2-fluorobenzyl)acetamide, compound 2: 2-[4,5-bis(2,4-dichlorophenyl)-2H-1,2,3-triazol-2-yl]-N-(4-fluorobenzyl)acetamide, compound 3: N-benzyl-2-[4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2H-1,2,3-triazol-2-yl]acetamide]), characterized in vitro as CB1 antagonists with high CB1 over CB2 selectivity, in the mouse GI tract. The action of compounds 1–3 was assessed in vitro (electrical field stimulated smooth muscle contractility of the mouse ileum and colon) and in vivo (whole GI transit time). Compound 1 decreased ileal (10−6 M) and colonic (10−7–10−6 M) smooth muscles contractility. Moreover, it prolonged whole GI transit. Compound 2 (10−10–10−8 M) slightly increased the amplitude of muscle contractions in the ileum, but at a higher concentration (10−6 M), the amplitude was decreased. Compound 2 reduced colonic contractility but accelerated GI transit. Compound 3 decreased the amplitude of intestinal muscle contractions in the ileum (10−6 M) and colon (10−10–10−6 M). Moreover, it increased the GI transit time in vivo. Triazole derivatives possess easily modifiable structure and interesting pharmacological action in the GI tract; further, alterations may enhance their efficacy at CB receptors and provide low side effect profile in clinical conditions.

Keywords

1,2,3-Triazoles Cannabinoid receptor CB1 antagonist SR141716A Rimonabant 

Notes

Author contributions

Designed the research study: JF, MS, DRH

Performed the research: JF, KL, MR, SA

Analyzed the data: JF, KL, AS, MZ

Wrote the paper: AS, MZ, JF, MS

All authors approved the final version of the manuscript.

Compliance with ethical standards

All procedures used in this study were performed in accordance with respective national guidelines and approved by the Local Ethical Committee (protocol number #M07102).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Bergamaschi MM, Queiroz RHC, Chagas MHN, Linares IMP, Arrais KC, de Oliveira DCG, Queiroz ME, Nardi AE, Huestis MA, Hallak JEC, Zuardi AW, Moreira FA, Crippa JAS (2014) Rimonabant effects on anxiety induced by simulated public speaking in healthy humans: a preliminary report. Hum Psychopharmacol 29(1):94–99.  https://doi.org/10.1002/hup.2374 CrossRefPubMedGoogle Scholar
  2. Coutts AA, Pertwee RG (1997) Inhibition by cannabinoid receptor agonists of acetylcholine release from the guinea-pig myenteric plexus. Br J Pharmacol 121(8):1557–1566.  https://doi.org/10.1038/sj.bjp.0701301 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Di Marzo V, Capasso R, Matias I, Aviello G, Petrosino S, Borrelli F, Romano B, Orlando P, Capasso F, Izzo AA (2008) The role of endocannabinoids in the regulation of gastric emptying: alterations in mice fed a high-fat diet. Br J Pharmacol 153(6):1272–1280.  https://doi.org/10.1038/sj.bjp.0707682 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Fichna J, Storr MA (2012) Brain-gut interactions in IBS. Front Pharmacol 3(July):1–13.  https://doi.org/10.3389/fphar.2012.00127 Google Scholar
  5. Fichna J, Sibaev A, Salaga M, Sobczak M, Storr M (2013a) The cannabinoid-1 receptor inverse agonist taranabant reduces abdominal pain and increases intestinal transit in mice. Neurogastroenterol Motil 25(8):550–559.  https://doi.org/10.1111/nmo.12158 CrossRefGoogle Scholar
  6. Fichna J, Wood JT, Papanastasiou M, Vadivel SK, Oprocha P, Sałaga M, Sobczak M, Mokrowiecka A, Cygankiewicz AI, Zakrzewski PK, Małecka-Panas E, Krajewska WM, Kościelniak P, Makriyannis A, Storr MA (2013b) Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study. PLoS One 8(12):e85073.  https://doi.org/10.1371/journal.pone.0085073 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Fichna J, Sobczak M, Mokrowiecka A, Cygankiewicz AI, Zakrzewski PK, Cenac N, Sałaga M, Timmermans JP, Vergnolle N, Małecka-Panas E, Krajewska WM, Storr M (2014) Activation of the endogenous nociceptin system by selective nociceptin receptor agonist SCH 221510 produces antitransit and antinociceptive effect: a novel strategy for treatment of diarrhea-predominant IBS. Neurogastroenterol Motil 26(11):1539–1550.  https://doi.org/10.1111/nmo.12390 CrossRefPubMedGoogle Scholar
  8. Fong TM, Heymsfield SB (2009) Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions. Int J Obes (2005) 33(9):947–955.  https://doi.org/10.1038/ijo.2009.132 CrossRefGoogle Scholar
  9. Gill EW, Paton WDM, Pertwee RG (1970) Preliminary experiments on the chemistry and pharmacology of cannabis. Nature 228(5267):134–136.  https://doi.org/10.1038/228134a0 CrossRefPubMedGoogle Scholar
  10. Hou D-R, Alam S, Kuan T-C, Ramanathan M, Lin T-P, Hung M-S (2009) 1,2,3-Triazole derivatives as new cannabinoid CB1 receptor antagonists. Bioorg Med Chem Lett 19(3):1022–1025.  https://doi.org/10.1016/j.bmcl.2008.11.029 CrossRefPubMedGoogle Scholar
  11. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54(2).  https://doi.org/10.1124/pr.54.2.161. Retrieved from http://pharmrev.aspetjournals.org/content/54/2/161.long.
  12. Izzo AA, Coutts AA (2005) Cannabinoids and the digestive tract. Handb Exp Pharmacol (168) 573–98. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16596788
  13. Izzo AA, Sharkey KA (2010) Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther 126(1):21–38.  https://doi.org/10.1016/j.pharmthera.2009.12.005 CrossRefPubMedGoogle Scholar
  14. Izzo AA, Mascolo N, Borrelli F, Capasso F (1998) Excitatory transmission to the circular muscle of the guinea-pig ileum: evidence for the involvement of cannabinoid CB1 receptors. Br J Pharmacol 124(7):1363–1368.  https://doi.org/10.1038/sj.bjp.0701964 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Izzo AA, Mascolo N, Borrelli F, Capasso F (1999a) Defaecation, intestinal fluid accumulation and motility in rodents: implications of cannabinoid CB1 receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 359(1):65–70 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9933153 CrossRefGoogle Scholar
  16. Izzo AA, Mascolo N, Pinto L, Capasso R, Capasso F (1999b) The role of cannabinoid receptors in intestinal motility, defaecation and diarrhoea in rats. Eur J Pharmacol 384(1):37–42.  https://doi.org/10.1016/S0014-2999(99)00673-1 CrossRefPubMedGoogle Scholar
  17. Jagerovic N, Hernandez-Folgado L, Alkorta I, Goya P, Navarro M, Serrano A, Rodriguez de Fonseca F, Dannert MT, Alsasua A, Suardiaz M, Pascual D, Martín MI (2004) Discovery of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole, a novel in vivo cannabinoid antagonist containing a 1,2,4-triazole motif. J Med Chem 47(11):2939–2942.  https://doi.org/10.1021/jm031099y CrossRefPubMedGoogle Scholar
  18. Kendall DA, Yudowski GA (2017) Cannabinoid receptors in the central nervous system: their signaling and roles in disease. Front Cell Neurosci 10:294.  https://doi.org/10.3389/fncel.2016.00294
  19. Lee Y, Jo J, Chung HY, Pothoulakis C, Im E (2016) Endocannabinoids in the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 311(4):G655–G666.  https://doi.org/10.1152/ajpgi.00294.2015 CrossRefPubMedGoogle Scholar
  20. Mackie K (2008) Cannabinoid receptors: where they are and what they do. J Neuroendocrinol 20(s1):10–14.  https://doi.org/10.1111/j.1365-2826.2008.01671.x CrossRefPubMedGoogle Scholar
  21. McCallum RW, Soykan I, Sridhar KR, Ricci DA, Lange RC, Plankey MW (1999) Delta-9-tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study. Aliment Pharmacol Ther 13(1):77–80 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9892882 CrossRefPubMedGoogle Scholar
  22. Nye JS, Seltzman HH, Pitt CG, Snyder SH (1985) High-affinity cannabinoid binding sites in brain membranes labeled with [3H]-5′-trimethylammonium delta 8-tetrahydrocannabinol. J Pharmacol Exp Ther 234(3):784–791PubMedGoogle Scholar
  23. Pertwee RG (2001) Cannabinoids and the gastrointestinal tract. Gut 48(6):859–867.  https://doi.org/10.1136/gut.48.6.859 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Pertwee RG (2005) Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 76(12):1307–1324.  https://doi.org/10.1016/j.lfs.2004.10.025 CrossRefPubMedGoogle Scholar
  25. Pertwee RG (2015) Endocannabinoids and their pharmacological actions . Springer International Publishing, pp 1–37.  https://doi.org/10.1007/978-3-319-20825-1_1
  26. Pertwee RG, Stevenson LA, Elrick DB, Mechoulam R, Corbett AD (1992) Inhibitory effects of certain enantiomeric cannabinoids in the mouse vas deferens and the myenteric plexus preparation of guinea-pig small intestine. Br J Pharmacol 105(4):980–984. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1908724&tool=pmcentrez&rendertype=abstract.  https://doi.org/10.1111/j.1476-5381.1992.tb09088.x CrossRefPubMedPubMedCentralGoogle Scholar
  27. Pertwee RG, Fernando SR, Nash JE, Coutts AA (1996) Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine. Br J Pharmacol 118(8):2199–2205.  https://doi.org/10.1111/j.1476-5381.1996.tb15663.x Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8864562 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Popa S-L, Dumitrascu DL (2015) Anxiety and IBS revisited: ten years later. Clujul Med (1957) 88(3):253–257.  https://doi.org/10.15386/cjmed-495 CrossRefGoogle Scholar
  29. Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand J-P, Soubrie P (2003) Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol 284(2):R345–R353.  https://doi.org/10.1152/ajpregu.00545.2002 CrossRefPubMedGoogle Scholar
  30. Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Néliat G, Caput D, Ferrara P, Soubrié P, Brelière JC, Le Fur G (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350(2–3):240–244.  https://doi.org/10.1016/0014-5793(94)00773-X CrossRefPubMedGoogle Scholar
  31. Shook JE, Burks TF (1989) Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents. J Pharmacol Exp Ther 249(2)Google Scholar
  32. Sibaev A, Yüce B, Kemmer M, Van Nassauw L, Broedl U, Allescher HD, Göke B, Timmermans JP, Storr M (2009) Cannabinoid-1 (CB1) receptors regulate colonic propulsion by acting at motor neurons within the ascending motor pathways in mouse colon. Am J Physiol Gastrointest Liver Physiol 296(1):G119–G128.  https://doi.org/10.1152/ajpgi.90274.2008 CrossRefPubMedGoogle Scholar
  33. Storr M, Sibaev A, Marsicano G, Lutz B, Schusdziarra V, Timmermans J-P, Allescher HD (2003) Cannabinoid receptor type 1 modulates excitatory and inhibitory neurotransmission in mouse colon. Am J Physiol Gastrointest Liver Physiol 286(1):110G–1117.  https://doi.org/10.1152/ajpgi.00148.2003 CrossRefGoogle Scholar
  34. Storr MA, Bashashati M, Hirota C, Vemuri VK, Keenan CM, Duncan M, Lutz B, Mackie K, Makriyannis A, Macnaughton WK, Sharkey KA (2010) Differential effects of CB(1) neutral antagonists and inverse agonists on gastrointestinal motility in mice. Neurogastroenterol Motil 22(7):787–796, e223.  https://doi.org/10.1111/j.1365-2982.2010.01478.x CrossRefPubMedPubMedCentralGoogle Scholar
  35. Svíženská I, Dubový P, Šulcová A (2008) Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures—a short review. Pharmacol Biochem Behav 90(4):501–511.  https://doi.org/10.1016/j.pbb.2008.05.010 CrossRefPubMedGoogle Scholar
  36. Thomas A, Ross RA, Saha B, Mahadevan A, Razdan RK, Pertwee RG (2004) 6″-Azidohex-2″-yne-cannabidiol: a potential neutral, competitive cannabinoid CB1 receptor antagonist. Eur J Pharmacol 487(1–3):213–221.  https://doi.org/10.1016/j.ejphar.2004.01.023 CrossRefPubMedGoogle Scholar
  37. Van Gaal L, Pi-Sunyer X, Després J-P, McCarthy C, Scheen A (2008) Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients. Diabetes Care 31 (supplement 2)Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Agata Szymaszkiewicz
    • 1
  • Marta Zielinska
    • 1
  • Kun Li
    • 2
  • Mani Ramanathan
    • 3
  • Safiul Alam
    • 3
  • Duen-Ren Hou
    • 3
  • Jakub Fichna
    • 1
  • Martin Storr
    • 2
    • 4
    • 5
    • 6
  1. 1.Department of Biochemistry, Faculty of MedicineMedical University of LodzLodzPoland
  2. 2.Snyder Institute for Chronic Diseases, Division of Gastroenterology, Department of MedicineUniversity of CalgaryCalgaryCanada
  3. 3.Department of ChemistryNational Central UniversityJhongli CityTaiwan
  4. 4.Walter Brendel Center of Experimental MedicineLudwig Maximilians University MunichMunichGermany
  5. 5.Center of EndoscopyStarnbergGermany
  6. 6.Department of Medicine, Division of GastroenterologyLudwig Maximilians University of MunichMunichGermany

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