Comparison of in vitro actions with behavioral effects of antimuscarinic agents

In vitro potencies of a series of muscarinic antagonists were compared with their effects on operant behavior. Ki values for inhibition of [3H]N-methylscopolamine binding in N4TG1 neuroblastoma cells correlated positively with ED50 values for the inhibition of carbachol-induced alpha-amylase release from pancreatic acini cells and with KB values for inhibition of acetylcholine-induced contractions of guinea pig ileum. The rank order of potency for inhibition of [3H]N-methylscopolamine binding was quinuclidinyl benzilate = quinuclidinyl xanthene-9-carboxylate greater than (methyl atropine = atropine) greater than benactyzine greater than azaprophen greater than (adiphenine = aprophen) greater than pirenzepine greater than ethyl aprophen. The M1 antagonist, pirenzepine, was a weak inhibitor in the guinea pig ileum and alpha-amylase assays relative to its ability to inhibit [3H]N-methylscopolamine binding; azaprophen exhibited the opposite relationship. Lever-press responses of rats were maintained by food delivery under a schedule requiring 10 responses for each food presentation. The high response rates engendered by this schedule were decreased in a dose-dependent manner by all compounds. The order of potency for this behavioral effect (ED50) was atropine = azaprophen greater than aprophen greater than (methyl atropine = benactyzine) greater than pirenzepine greater than adiphenine. Behavioral depressant actions of the antimuscarinics correlated positively with their potencies in inhibiting alpha-amylase secretion. Pirenzepine was unique in being relatively more potent in its behavioral effects than in its actions in vitro. In contrast to the other antimuscarinic agents studied, the benzilates, benactyzine, aprophen and adiphenine, but not azaprophen, increased behavioral response rates.(ABSTRACT TRUNCATED AT 250 WORDS)