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Novel derivatives of 1,2,3-triazole, cannabinoid-1 receptor ligands modulate gastrointestinal motility in mice.
Naunyn Schmiedebergs Arch Pharmacol. 2018 04; 391(4):435-444.NS

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.

Authors+Show Affiliations

Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.Snyder Institute for Chronic Diseases, Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, AB, Canada.Department of Chemistry, National Central University, 300 Jhong-Da Road, Jhongli City, Taoyuan, Taiwan.Department of Chemistry, National Central University, 300 Jhong-Da Road, Jhongli City, Taoyuan, Taiwan.Department of Chemistry, National Central University, 300 Jhong-Da Road, Jhongli City, Taoyuan, Taiwan.Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.Snyder Institute for Chronic Diseases, Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, AB, Canada. martin.storr@med.uni-muenchen.de. Walter Brendel Center of Experimental Medicine, Ludwig Maximilians University Munich, Munich, Germany. martin.storr@med.uni-muenchen.de. Center of Endoscopy, Starnberg, Germany. martin.storr@med.uni-muenchen.de. Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany. martin.storr@med.uni-muenchen.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29404698

Citation

Szymaszkiewicz, Agata, et al. "Novel Derivatives of 1,2,3-triazole, Cannabinoid-1 Receptor Ligands Modulate Gastrointestinal Motility in Mice." Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 391, no. 4, 2018, pp. 435-444.
Szymaszkiewicz A, Zielinska M, Li K, et al. Novel derivatives of 1,2,3-triazole, cannabinoid-1 receptor ligands modulate gastrointestinal motility in mice. Naunyn Schmiedebergs Arch Pharmacol. 2018;391(4):435-444.
Szymaszkiewicz, A., Zielinska, M., Li, K., Ramanathan, M., Alam, S., Hou, D. R., Fichna, J., & Storr, M. (2018). Novel derivatives of 1,2,3-triazole, cannabinoid-1 receptor ligands modulate gastrointestinal motility in mice. Naunyn-Schmiedeberg's Archives of Pharmacology, 391(4), 435-444. https://doi.org/10.1007/s00210-018-1465-9
Szymaszkiewicz A, et al. Novel Derivatives of 1,2,3-triazole, Cannabinoid-1 Receptor Ligands Modulate Gastrointestinal Motility in Mice. Naunyn Schmiedebergs Arch Pharmacol. 2018;391(4):435-444. PubMed PMID: 29404698.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel derivatives of 1,2,3-triazole, cannabinoid-1 receptor ligands modulate gastrointestinal motility in mice. AU - Szymaszkiewicz,Agata, AU - Zielinska,Marta, AU - Li,Kun, AU - Ramanathan,Mani, AU - Alam,Safiul, AU - Hou,Duen-Ren, AU - Fichna,Jakub, AU - Storr,Martin, Y1 - 2018/02/05/ PY - 2017/08/16/received PY - 2018/01/09/accepted PY - 2018/2/7/pubmed PY - 2018/11/27/medline PY - 2018/2/7/entrez KW - 1,2,3-Triazoles KW - CB1 antagonist KW - Cannabinoid receptor KW - Rimonabant KW - SR141716A SP - 435 EP - 444 JF - Naunyn-Schmiedeberg's archives of pharmacology JO - Naunyn Schmiedebergs Arch Pharmacol VL - 391 IS - 4 N2 - 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. SN - 1432-1912 UR - https://www.unboundmedicine.com/medline/citation/29404698/Novel_derivatives_of_123_triazole_cannabinoid_1_receptor_ligands_modulate_gastrointestinal_motility_in_mice_ L2 - https://dx.doi.org/10.1007/s00210-018-1465-9 DB - PRIME DP - Unbound Medicine ER -