Studies on Serotonin (5-HT)3-Receptor Antagonist Effects of Enantiomers of 4,5,6,7-Tetrahydro-lH-Benzimidazole Derivatives

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Abstract
We assessed the 5-HT3-receptor antagonist effects of 4, 5, 6, 7-1H-benzimidazole compounds which are derivatives of YM060, a potent and selective 5-HT3-receptor antagonist, in isolated guinea pig colon. YM114 (KAE-393), YM-26103-2, YM-26308-2 (3 × 10-9 to 3 × 10-8 M) produced concentration-dependent shifts to the right of the dose-response curves for both 5-HT and 2-methyl-5-HT (2-Me-5-HT). YM114 (pA2=9.08 against 5-HT, pA2=8.88 against 2-Me-5-HT), YM-26103-2 (pA2=8.27 against 5-HT, pA2 = 8.19 against 2-Me-5-HT), and YM-26308-2 (pA2 = 8.58 against 5-HT, pA2 = 8.4 against 2-Me-5-HT) showed similar pA2 values irrespective of the agonist used, suggesting that they have 5-HT3-receptor blocking activity irrespective of the N-position at the aromatic ring. Since these compounds have an asymmetric center, their enantiomers exist. The S-isomers were one to three orders of magnitude less potent than the respective R-isomer compounds, indicating that the stereochemical configuration of 4, 5, 6, 7-tetrahydro-1Hbenzimidazoles is an important determinant of their affinity for 5-HT3 receptors. These results suggest that the highly potent 5-HT3 receptor antagonism and high selectivity for 5-HT3 receptors of 4, 5, 6, 7-tetrahydro-1H-Benzimidazole derivatives are conserved irrespective of the position of the nitrogen atom in the aromatic ring and that 5-HT3, recentors favor the R-isometric conformation of these compounds.