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The use of 4‐diphenylacetoxy‐N‐(2‐chloroethyl)‐piperidine (4‐DAMP mustard) for estimating the apparent affinities of some agonists acting at muscarinic receptors in guinea‐pig ileum
Author(s) -
Barlow R.B.,
McMillen Louise S.,
Veale M.A.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12229.x
Subject(s) - muscarinic acetylcholine receptor , hexamethonium , carbachol , chemistry , iodide , ileum , agonist , ammonium , receptor , biochemistry , inorganic chemistry , organic chemistry
1 4‐Diphenylacetoxy‐ N ‐(2‐chloroethyl)‐piperidine (4‐DAMP mustard), which is known to block muscarinic M 3 receptors in preference to muscarinic M 2 receptors, was used to estimate the apparent affinity constants of some agonists acting at muscarinic receptors in guinea‐pig ileum. Estimates for carbachol and n ‐pentyl‐trimethyl ammonium iodide were similar to published values obtained in similar conditions: those for n ‐hexyl‐trimethyl ammonium iodide were slightly lower. 2 The results for the agonists, n ‐pentyl‐ and n ‐hexyl‐trimethyl ammonium iodides and for the partial agonist, n ‐heptyl‐trimethyl ammonium iodide were not as regular as was suggested by Stephenson, though there is an overall increase in apparent affinity with chain length. 3 Estimates of apparent affinity may be affected by hexamethonium, usually present in experiments on ileum. Its absence had little effect on the results with carbachol but reduced the estimates obtained with n‐pentyl trimethyl ammonium, which has strong nicotinic effects compared with its muscarinic effects. On ileum treated with tetrodotoxin the values for n ‐pentyl trimethyl ammonium were similar to those obtained in the presence of hexamethonium (0.28 m m ): slightly higher estimates of affinity were obtained in the presence of indomethacin (2.8 μ m ). The nicotinic effects of n‐pentyl ammonium may involve the release of prostaglandins. 4 The estimates of apparent affinity did not depend on the method used to calculate them as the ‘null’ method and the ‘operational’ method give similar answers. Estimates of the transducer‐ratio for the partial agonist, n ‐heptyl‐trimethyl ammonium iodide, were numerically the same as those of its efficacy. 5 This work illustrates the use of 4‐DAMP mustard as a tool for measuring the apparent affinity of agonists acting at muscarinic M 3 receptors.