1 Isolated preparations of guinea-pig ileum and atria have been used to estimate the dose-ratios produced by antagonists at muscarinic receptors. Experiments with 4-diphenyl-acetoxy-N-methylpiperidine (4DAMP) metho-salts and with its isomer, 3DAMP methiodide, indicate that these are only slightly affected by the choice of physiological salt solution, the choice of agonist and the presence or absence of hexamethonium. 2 Methyl or chloro groups in the p-position of the two benzene rings in 4DAMP metho-salts markedly reduce affinity and selectivity. 3 When the two benzene rings are linked together, as in the fluorene-9-carboxylic ester, the affinity for the receptors in the atria is comparable with that of4DAMP methobromide but that for the ileum is about half, so the selectivity is reduced. When the rings are linked as in the xanthene-9-carboxylic ester, the affinity for receptors in both tissues is greater than that of 4DAMP methobromide but there is less selectivity. 4 When two molecules of 4DAMP are linked together by a polymethylene chain of from 4 to 12 carbon atoms the effects on affinity for muscarinic receptors in the guinea-pig ileum are different from those on affinity for muscarinic receptors in guinea-pig atria. The pentamethylene compound is the most selective: compared with 4DAMP methobromide it has slightly less affinity for receptors in the ileum but much less affinity for receptors in the atria. 5 The effects of the compounds in antagonizing the actions of carbachol on atrial rate are not markedly different from their effects in antagonizing its actions on the force of the atrial contractions.

1 In an attempt to obtain more selective antagonists acting at muscarinic M2-receptors, analogues of 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP methobromide) have been synthesized. These were tested, along with silabenzhexol, procyclidine, sila-procyclidine and AFDX-1 16, in dose-ratio experiments with guinea-pig isolated atria at 30'C and ileum at 30'C and 37°C. The agonist was carbachol and the selectivity was assessed from the difference between log K for receptors in ileum and log K for receptors in atria. 2 The selectivity was not related to the affinity and some weakly active compounds retained appreciable selectivity but no compound had greater selectivity than 4-DAMP methobromide or pentamethylene bis-(4-diphenylacetoxy-N-methylpiperidinium) bromide. 3 Structure-activity relations are discussed. There seem to be steric limits to affinity but there are no obvious indications of the structural features associated with selectivity. It is suggested that more selective drugs may be obtained by introducing groups which may reduce affinity.

No abstract

No abstract

1 The replacement of 4-hydroxy-N-methyl piperidine (HO NMe) in 4-diphenylacetoxy-Nmethyl piperidine (4-DAMP) metho-bromide by 4-hydroxy-but-2-ynylamines (HOCH2C= CCH2NR2) reduces the affinity for muscarine-sensitive acetylcholine receptors in guinea-pig ileum and atria. It does not abolish selectivity. The tertiary amines are more active and more selective than the corresponding quaternary salts. 2 Analogous derivatives of 4-hydroxy-but-2-ynylamines which lack the ester group (i.e. substituted 4-hydroxymethyl-propynyl amines) are less active and less selective. The quaternary compounds are more active than the tertiary bases. 3 The diphenylcarbamyl ester of 4-hydroxy-N-methylpiperidine methobromide has less than onethousandth of the activity of the diphenylacetyl ester (4-DAMP methobromide) and is not selective. 4 Although 4-diphenylacetoxy-butynyl dimethylamine is only about one-hundredth as active as 4-DAMP methobromide it appears to have comparable selectivity. It is an interesting compound because it is a tertiary amine and should cross membranes.