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Pharmacological analyses of endo-6-methoxy-8-methyl-8- azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1 H- benzimidazole-1- carboxylate hydrochloride (DAU 6285) at the 5-hydroxytryptamine4 receptor in the tunica muscularis mucosae of rat esophagus and ileum of guinea pig: role of endogenous 5-hydroxytryptamine

MV Waikar, SS Hegde, AP Ford and DE Clarke

Institute of Pharmacology, Syntex Research, Palo Alto, California.

Functional estimates of affinity for endo-6-methoxy-8-methyl-8- azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1H-benzimidazole-1- carboxyla te hydrochloride (DAU 6285) were made at the 5- hydroxytryptamine4 (5-HT4) receptor in isolated preparations of rat esophageal tunica muscularis mucosae (TMM) and guinea pig ileum. In the TMM, relaxation of carbachol-induced contracture by 5-HT4 receptor agonism of longitudinal muscle was recorded. Estimated pA2 values for DAU 6285 of 6.9 to 7.2 were tissue, time (1-3 hr equilibration) and agonist-independent. However, DAU 6285 increased the maximal response to 5-HT and 5-methoxytryptamine in the TMM and augmented the contractile tone to carbachol. These effects were not observed in guinea pig ileum, suggesting a tissue-dependent mechanism. [3a- Tropanyl]-1H-indole-3-carboxylic acid ester (tropisetron) and 2-methoxy- 4-amino-5-chloro-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205- 557), two other 5-HT4 receptor antagonists, mimicked the effects of DAU 6285. Mechanistic experiments suggest agonism by endogenous 5-HT, within the isolated TMM, to explain the effects of 5-HT4 receptor antagonists. Pretreatment of rats with parachlorophenylalanine to deplete endogenous 5-HT, prevented the effect of DAU 6285 on the maximal response to 5-HT and carbachol-induced tone. In conclusion, DAU 6285 acts as a silent, competitive antagonist at 5-HT4 receptors in rat TMM and guinea pig ileum. However, in the TMM, endogenously released 5- HT confounds interpretation. The TMM, as a quantitative assay system for 5-HT4 receptor agonists and antagonists may be improved by pretreating rats with parachlorophenylalanine.

Volume 264, Issue 2, pp. 654-661, 02/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics






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Copyright © 1993 by the American Society for Pharmacology and Experimental Therapeutics.