Comparison of the Antimuscarinic Action of p-Fluorohexahydrosiladifenidol in Ileal and Tracheal Smooth Muscle

Abstract

We investigated the ability of the muscarinic antagonist pfluorohexahydrosiladifenidol to inhibit muscarinic agonist-induced contractions and phosphoinositide hydrolysis in the guinea pig ileum and trachea. This antagonist displayed higher potency at blocking oxotremorine-M-induced contractions of the ileum compared with those of the trachea. When estimated using a simple model for competitive antagonism, the observed dissociation constant of p-fluorohexahydrosiladifenidol exhibited approximately 12-fold higher potency in the ileum compared with the trachea. We also investigated the ability of p-fluorohexahydrosiladifenidol to affect the inhibition of contraction caused by the known competitive muscarinic antagonist atropine. Using resultant analysis to analyze this interaction, we found that the true dissociation constant of p-fluorohexahydrosiladifenidol for competitively antagonizing oxotremorine-M-induced contractions in the ileum exhibited significantly lower potency than when calculated assuming a simple competitive model. In contrast, resultant analysis showed little difference between the true and observed potencies of p-fluorohexahydrosiladifenidol for antagonizing oxotremorine-M-induced contractions in the trachea. Using a simple competitive model, we found little difference in the observed dissociation constant of p-fluorohexahydrosiladifenidol for antagonizing oxotremorine-M-induced phosphoinositide hydrolysis in guinea pig ileum and bovine trachea. We also noted that p-fluorohexahydrosiladifenidol (0.3-1.0 M) moderately inhibited histamine-induced contractions of ileum but not of trachea. Our results suggest that p-fluorohexahydrosiladifenidol does not discriminate markedly between M 3 muscarinic receptors in the ileum and trachea and that it may posses a more potent, nonmuscarinic inhibitory effect on contraction in the ileum.

Muscarinic Agonists and Antagonists: Effects on Gastrointestinal Function

“…For example, the compound zamifenacin inhibits muscarinic agonist-induced contraction of the guinea-pig ileum, trachea, and urinary bladder with high (pK B ¼ 9.3), intermediate (pK B ¼ 8.2), and low potency (pK B ¼ 7.6), respectively (Wallis 1995;Watson et al 1995), and the compound p-F-HHSiD exhibits a similar pattern of selectivity with regard to ileum and trachea (Eglen et al 1990;Ehlert et al 2005b). These compounds exhibit high affinity for M 3 , low affinity for M 2 , and variable affinity for the other muscarinic subtypes when measured in radioligand binding assays on Chinese hamster ovary (CHO) cells stably expressing human muscarinic receptor subtypes.…”

“…This technique enables one to estimate the pK B of the competitive component based on the ability of the antagonist to interfere with the competitive effect of a purely competitive antagonist, like atropine, for example. When this approach was used on guinea-pig ileum and trachea to measure the competitive component of the inhibitory effect of p-F-HHSiD on muscarinic agonist-induced contraction, it was found that p-F-HHSiD exhibited similar pK B values for inhibition of agonist-induced contraction of ileum and trachea (Ehlert et al 2005b). Thus, there is no reason to suggest that p-F-HHSiD competitively antagonizes muscarinic responses with different affinities in different tissues.…”

“…p-F-HHSiD has been shown to inhibit histamine-induced contractions of the guinea-pig ileum, although its potency for doing so is less than that measured for inhibition of muscarinic agonist-induced contraction (Ehlert et al 2005b). The compound has also been shown to inhibit GTPgS-stimulated I cat in guinea pig ileal smooth muscle suggesting that it can directly block the cationic channel.…”

“…In contrast to the variable pK B value of p-F-HHSiD noted in contractile studies, similar pK B values were estimated when the antagonism of muscarinic agonistinduced phosphoinositide hydrolysis in guinea-pig ileum and bovine trachea was measured (Ehlert et al 2005b). The corresponding pK B values were approximately the same as the binding affinity (pK D value) of the human M 3 muscarinic receptor.…”

Synthesis of a quaternary bis derivative of imipramine as a novel compound with potential anti-enuretic effect

“…Male albino guinea pigs with 300–450 g body weight were used. They were fasted for 24 h and fed with water as required 14,15 . The animals were euthanized by stunning, incision into the carotid and exsanguination.…”