SOME DIFFERENTIAL-EFFECTS OF 4-DIPHENYLACETOXY-N-(2-CHLOROETHYL)-PIPERIDINE HYDROCHLORIDE ON GUINEA-PIG ATRIA AND ILEUM

Abstract— 4‐Diphenylacetoxy‐N‐(2‐chloroethyl)‐piperidine hydrochloride (I) cyclizes at neutral pH to form an aziridinium salt. The formation and breakdown of the salt depend on the temperature (in the range 25 to 37°C). In solution at 30 C., peak levels, corresponding to 60–80% conversion, are reached after around 60 min and the half‐life exceeds 100 min. In the presence of 0.9% NaCl conversion was reduced to 45–60%. I blocks muscarinic receptors in guinea‐pig ileum and atria irreversibly and it is possible to produce dose‐ratios on ileum with 10 nM I which are about 100 times those on atria. After about 30 min exposure to solutions of I (prepared 15–20 min previously so that formation of aziridinium ions is well‐established) the graph of log (dose‐ratio) against time is linear and similar plots were obtained with two different agonists, carbachol and ethoxyethyltrimethylammonium. With results for the ileum, extrapolation of the line suggests that it does not start from zero (dose‐ratio = 1): this is because of an initial relatively rapid reversible block. This early phase is similar to that seen on ileum with 10 nM 4DAMP methobromide, which is a competitive antagonist, so is probably caused by competitive block by the aziridinium ion, which closely resembles 4DAMP metho‐salts. The subsequent irreversible phase should be caused by alkylation of the receptors. I is easy to make and should be a valuable tool for the study of muscarinic receptors. 1990 Royal Pharmaceutical Society of Great Britain