A further search for selective antagonists at M₂‐muscarinic receptors

Abstract

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.

Differential Affinities of AF-DX 116, Atropine and Pirenzepine for Muscarinic Receptors of Guinea Pig Gastric Fundus, Atria and Urinary Bladder: Might Atropine Distinguish among Muscarinic Receptor Subtypes?

“…AF-DX 116 appears to discriminate among the muscarinic receptor subclasses of the three tissues examined. These results are in agreement with those obtained both in whole-tissue pharmacology and in radioli gand-binding experiments, which indicate a marked preference of the drug for atrial mus carinic M2 receptors compared with those of smooth muscles [11,15,23,24], The signifi cant difference between the pA2 values of urinary bladder and atria found with AF-DX 116 further supports the heterogeneity of muscarinic receptors in peripheral effector organs, in agreement with previous results obtained in both tissue pharmacology [25] and binding studies [16,17,26]. In agree ment with these data, Angeli et al [27], by studying enantiomers of chiral muscarinic agonists, have shown that atrial receptors differ from bladder receptors.…”

Expression and pharmacological characterization of the human M1 muscarinic receptor in Saccharomyces cerevisiae

“…The structural integrity of the muscarinic binding sites detected in transformants was assessed by determining the affinities of a series of muscarinic ligands in competition binding studies with [3H]-NMS. The ligands included two agonists (carbachol and oxotremorine), the non-selective antagonist atropine, and 3 selective antagonists (pirenzepine, 4-DAMP and methoctramine) which distinguish 3 subclasses of muscarinic binding sites in mammalian tissues [17][18][19]. The competition curves are presented in Fig.…”

Effects of chain‐length and unsaturation on affinity and selectivity at muscarinic receptors

“…There is an increase in affinity (more than obtained by replacing phenyl by cyclohexyl; Barlow & Shepherd, 1986), but there is a loss of selectivity. The very high selectivity of p-fluorohexahydro-sila-diphenidol can also be seen but the compound has relatively low affinity, less than that of silabenzhexol or silaprocyclidine (Barlow & Shepherd, 1986).…”

“…There is an increase in affinity (more than obtained by replacing phenyl by cyclohexyl; Barlow & Shepherd, 1986), but there is a loss of selectivity. The very high selectivity of p-fluorohexahydro-sila-diphenidol can also be seen but the compound has relatively low affinity, less than that of silabenzhexol or silaprocyclidine (Barlow & Shepherd, 1986). The value for receptors in ileum (log K = 7.6) is comparable with that of diphenylhydroxymethyl-prop-3-ynyl-trimethyl-ammonium (log K = 7.3;Barlow et al, 1988), which has a C-CC-C chain instead of Si-C-C-C, but this compound has no selectivity (for atria log K = 7.4).…”

“…Macmiflan Press Ltd, 1990 (Barlow & Shepherd, 1986). The agonist, carbachol, was added by relays operated from a Commodore 128 microcomputer and allowed to act for 5 min: doses were given once every 15 min, with a second wash 10min from the start of the cycle.…”