A search for selective antagonists at M₂ muscarinic receptors

Abstract

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.

Reversal of haemorrhagic shock in rats by cholinomimetic drugs

“…injection of mecamylamine, which is a selective antagonist at nicotinic receptors (Brezenoff & Caputi, 1980;Matta et al, 1987). Whereas atropine (an M,-and M2-muscarinic antagonist), pirenzepine, a more selective Ml-muscarinic antagonist (Brown et al, 1980;Hammer et al, 1980;Doods et al, 1987), and 4-DAMP, a selective M2-muscarinic antagonist (Barlow & Shepherd, 1985;Brezenoff et al, 1988) did not inhibit them. We have no obvious explanation for such a discrepancy, or for the finding that in our experimental conditions, oxotremorine seems to act through the activation of nicotinic receptors.…”

A further search for selective antagonists at M2‐muscarinic receptors

“…Iftwo molecules are linked together with a pentamethylene chain a compound (bis-5 4-DAMP bromide) is obtained which is weaker but more selective (Barlow & Shepherd, 1985). In this paper the results obtained in a further search for compounds which differentiate between muscarinic receptors in guinea-pig ileum and guinea-pig atria are presented.…”

The selectivity of the (−)‐and (+)‐forms of hyoscine methiodide and of hyoscyamine camphorsulphonate for muscarinic (M2) receptors

“…The temperature was 29.8 ± 0.3OC and the spontaneous contractions were recorded isometrically with a load of about 0.2 g: action potentials were also recorded and the time required for 50 beats was continuously printed out (Barlow & Kitchen, 1982: Barlow & Shepherd, 1985. These methods are similar to those previously described (Barlow et al, 1976;Barlow & Kitchen 1982) except that, as described by Barlow & Shepherd (1985), Krebs solution, aerated with a mixture of 95% 02 and 5% CO2, was used for all tissues. No hexamethonium was present but in this work the solution contained 5 M norphenylephrine, which prevented the gradual slowing down of the spontaneously beating atria during the experiment.…”

“…There is considerable variation in the estimates of selectivity, however, and although pentamethylene bis-4DAMP bromide appears to be more selective that 4DAMP methobromide (Barlow & Shepherd, 1985), there has not yet emerged, even after 10 years, a compound which has say 100 times the affinity for ileum compared with atria. Is there perhaps, after all, only one type of M2-receptor with the differences in affinity caused by the way the experiments have been done or perhaps attributable to some physical properties of the compounds which affect their distribution?…”