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

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.

1,2,3-Triazole derivatives as new cannabinoid CB1 receptor antagonists.

This letter reports the new entry of novel 1,2,3-triazole derivatives as CB1 receptor antagonists. The design, synthesis and biological evaluation of N1 and N2 substituted 1,2,3-trizoles are described. The N2 substituted, symmetrical 1,2,3-triazoles are more potent ligands than the unsymmetrical analogues. The in vitro activity of these triazoles is further improved by inserting a methylene group between the central core and the carbonyl side chain. The most potent antagonists prepared in this series (IC(50)<20 nM) are the triazoles containing benzyl amides. These triazoles also show excellent selectivity between CB1 and CB2 receptors (IC(50)>10 microM for CB2; CB2/CB1>1000).