The effects of replacing ester by amide on the biological properties of compounds related to acetylcholine.
1 Replacement of ester by amine 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 composition 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--0--bond, though the hydration of the bond may also be important.
D000109:Acetylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000110:Acetylcholinesterase / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001001:Anura; D055598:Chemical Phenomena; D002621:Chemistry; D004593:Electrophorus; D004952:Esters / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011896:Rana temporaria; D011950:Receptors, Cholinergic / Q000187:drug effects; D013329:Structure-Activity Relationship
D000577:Amides; D004952:Esters; D011950:Receptors, Cholinergic; D000110:Acetylcholinesterase; D000109:Acetylcholine