The Effects of Replacing Ester by Amide on the Biological Properties of Compounds Related to Acetylcholine

Abstract

1 Replacement of ester by amide in series of derivatives of diphenylacetic acid reduces the affinity for muscarine-sensitive. acetylcholine receptors of the guinea-pig ileum from 40-to 100-fold. With similar series of phenylacetic acid the reduction is only 2-to 4-fold. In both series changes in the comnposition of the onium group produce similar changes in the affinity of amides-and esters and it appears that the stiffness of the amide bond reduces the binding of the phenyl groups at the far end of the molecule from the onium atom. 2 Replacement of ester by amide in similar series of acetyl compounds reduces activity on the guinea-pig ileum over 1000-fold and on the frog rectus over 50-fold. Compounds with larger onium groups are antagonists on both preparations with log affinity constant around 3. The amides have similar affinity for electric eel acetylcholinesterase. 3 The amides are slightly bigger than the esters in solution and slightly more hydrophilic. 4 Replacement of ester by amide in acetylcholine reduces the proportion of gauche conformer about the C-C-bond from 100% to 39%. 5 The ability of acetylcholine to activate receptors is thought to depend on some degree of flexibility in the -CO-O-bond, though the hydration of the bond may also be important.

Temperature Coefficients of Affinity and Entropies of Adsorption for Enantiomeric Pairs of Compounds Acting at Muscarinic Receptors in the Guinea‐pig Ileum

“…with a similar series of amides of diphenylacetic acid (Barlow, Bremner & Soh, 1978), that large onium groups are associated with an endothermic binding process.…”

“…The effect of temperature on log affinity constant (A log K) is indicated by the increment in log (doseratio -1) because the compounds are competitive antagonists and the dose-ratio = I + BK (Gaddum, 1937;Schild, 1949) with a similar series of amides of diphenylacetic acid (Barlow, Bremner & Soh, 1978), that large onium groups are associated with an endothermic binding process.…”

The Actions of Some Esters of 4‐hydroxyquinuclidine on Guinea‐pig Ileum, Atria and Rat Fundus Strip

“…p and M are common to both sets and the dose-ratio is given by the ratio of the values of K (Waud & Parker,, 1971;Barlow 1975) Experiments with electric eel acetylcholinesterase These were carried out as described by Barlow, Bremner & Soh (1978). The compounds were mostly poor substrates when studied by electrometric titration (pH 7.4).…”

“…These estimates appear to be in the same range as those obtained from the between experiment variance. For instance standard errors of about 10% were obtained by Barlow et al (1978) from four sets of electrometric titrations in which four concentrations of substrate were tested in duplicate. In similar work with mixed substrate experiments followed spectrophotometrically, Barlow (1978) observed standard errors in log affinity constant (-log K') of 0.01 to 0.05 log units (again usually based on 4 estimates).…”

PROCEEDINGS OF THE British Pharmacological Society

“…In tissues where more receptors are occupied the limit will be lower. On the frog rectus, which has a very low receptor reserve (Michelson & Shelkovnikov, 1976), the triethylammonium and ethylpiperidinium compounds are partial agonists (Barlow, Bremner & Soh, 1977). Cytosine arabinoside (Ara-C) is a nucleoside analogue with useful antileukaemic activity in man (Armentrout & Burns, 1974).…”