Studies on serotonin (5-HT)3-receptor antagonist effects of enantiomers of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives.
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 x 10(-9) to 3 x 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-1H-benzimidazoles 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 receptors favor the R-isometric conformation of these compounds.
Kamato
T
T
Neuroscience and Gastrointestinal Research Laboratory, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Ito
H
H
Suzuki
T
T
Miyata
K
K
Honda
K
K
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D012501:Saphenous Vein / Q000187:drug effects; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D014132:Trachea / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D012702:Serotonin Antagonists; C071315:ramosetron