Comparative study of the affinities of the 5-HT3 receptor antagonists, YM060, YM114 (KAE-393), granisetron and ondansetron in rat vagus nerve and cerebral cortex

Abstract The 5-HT 3 receptor blocking properties of YM060, YM114 (KAE-393), granisetron and ondansetron were examined in the vagus nerve and cerebral cortex of rats. 5-HT and 2-methyl-5-HT induced dose-dependent depolarizations of rat isolated vagus nerve with EC 50 values of2.53 (1.93–3.33) × 10 −6 and 4.03 (2.87–5.66) × 10 −6 M, respectively. YM060, YM114 and granisetron dose-dependently antagonized the depolarization of the rat vagus nerve induced by 5-HT, with decreases in the slope and maximal response at higher concentrations. Apparent pA 2 values for these antagonists were 10.27 ± 0.09, 10.12 ± 0.16 and 9.44 ± 0.40, respectively. Ondansetron produced a clear rightward shift of the concentration-response curve to 5-HT. The pA 2 value was 8.63 (8.23–9.68). YM060 and YM114 at up to 10 −5 M produced no significant depression of the depolarizing responses to DMPP and GABA. YM060, YM114, granisetron and Ondansetron displaced specific binding of [ 3 H]GR65630 to rat cortical membranes with p Ki values of 10.48 (10.41–10.57), 10.24 (10.18–10.28), 9.15 (9.02–9.28) and 8.70 (8.64–8.77), respectively. An excellent correlation ( r = 0.97) was obtained between pA 2 values in the vagus nerve and p Ki values in the cerebral cortex. YM060, YM114, granisetron and ondansetron showed low affinities for 5-HT 1A , 5-HT 2 receptor, adrenergic α 1 , α 2 , dopamine D 2 , muscarinic M 2 , μ-opioid, benzodiazepine and histamine H 1 receptors. These results support the possibility that the same type of 5-HT 3 receptor occurs in rat vagus nerve and cerebral cortex. Keywords—5-HT 3 receptor, vagus nerve, cerebral cortex, YM060 {(−)-(R)-5-[(1-methyl-1H-indol-3-yl)-carbonyl]-4, 5,6,7-tetrahydro-1H-benzimidazole monohydrochloride}, YM114 (KAE-393) {(−)-(R)-5-[(1-indolinyl)carbonyl]-4, 5,6,7-tetrahydro-1H-benzimidazole monohydrochloride}