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.
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.
Waikar
M V
MV
Institute of Pharmacology, Syntex Research, Palo Alto, California.
Hegde
S S
SS
Ford
A P
AP
Clarke
D E
DE
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004305:Dose-Response Relationship, Drug; D004947:Esophagus / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009092:Mucous Membrane / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*
D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C074390:DAU 6285; D012701:Serotonin