The affinity of some acetylenic analogues of 4‐DAMP methobromide for muscarinic receptors in guinea‐pig ileum and atria

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.

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

“…Increasing the size of the onium group from dimethylamino to pyrrolidino, however, reduces affinity. This is similar to what is seen with the corresponding butynes (Barlow et al, 1988) but unlike what is observed with choline derivatives (Abramson et al, 1969). These compounds all have much less affinity than 4-DAMP methobromide.…”

“…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).…”

“…This was treated with dimethylaminomethanol in the presence of cupric acetate to form the 3-dimethylaminomethyl compound, which was converted back to a diacetylene by removal of the thioethyl group with sodamide in liquid ammonia. The 4-dimethylaminomethyl-but-1,3-diyne was isolated and treated with butyl-lithium in ether and the lithioderivative was reacted with benzophenone, as in previous work (Barlow et al, 1988) to form 1,1-diphenyl-1-hydroxy-2,4-hexadiynyl dimethylamine.…”

“…The distances will depend on the number of atoms present and the spatial arrangement will depend on whether they form part of a ring and whether the bonds are saturated or unsaturated. Results obtained with some acetylenic analogues of 4-DAMP MeBr (Barlow et al, 1988) suggested that whereas 4-DAMP MeBr is more active than 4-DAMP base, the tertiary base was more active than the quaternary salt with longer compounds. Diphenyl-acetoxybutynyl dimethylamine was more active than its trimethylammonium analogue and although it was very much less active than 4-DAMP MeBr it had similar selectivity, being about 10 times as active on ileum as on atria.…”

Selective blockade of M2 and M3 muscarinic receptors by hexahydrobenzyl‐ fourdapine and a comparison with zamifenacin

“…The atria were set up as described by Edinburgh Staff (1974) in Krebs solution containing norphenylephrine (5 gM: Barlow & Shephard, 1986;Barlow et al, 1988), aerated with a mixture of oxygen (95%) and carbon dioxide (5%). The volume of the bath was about 21 ml and the contractions were recorded isotonically with a load of about 0.5 g. The temperature was 30'C.…”