Relationships between chemical structure and affinity for postganglionic acetylcholine receptors of the guinea-pig ileum.

1 Some phenylacetyl, diphenylacetyl, benziloyl and (+/-)-cyclohexylphenylglycolloyl esters have been made with 2- and 3-hydroxymethylpyrrolidines, 3-hydroxymethyl-N-methylpiperidine, piperidin-3-ols, piperidin-4-ols, 2,2,6,6-tetramethyl-N-methylpiperidin-4-ol, tropine, pseudotropine and quinuclidin-3-ol, and the affinity of these compounds and of their metho- and etho- derivatives has been measured for postganglionic acetylcholine receptors of the guinea-pig isolated ileum.2 Some of the compounds were very active indeed; the benziloyl esters of N-methylpiperidin-4-ol methiodide, tropine methiodide, and quinculidin-3-ol, and the (+/-)-cyclohexylphenylglycolloyl esters of N-methylpiperidin-4-ol and its methiodide had affinity constants greater than 10(10).3 The effects of inserting an additional methylene group onto the nitrogen were extremely variable, ranging from a decrease in log K of 1.64 units to an increase of 0.97 units. The effects of replacing hydrogen by phenyl in the acid portion ranged from an increase of 1.04 units to an increase of 3.06 units and of replacing hydrogen by hydroxyl from a decrease of 0.09 units to an increase of 1.94 units.4 The extent of the variation in the effects of a particular change in structure on affinity does not appear to be any different in these relatively rigid compounds from that observed with the same changes in open-chain aminoalcohols.5 Reasons for the variable effects of groups on affinity are discussed. If differences in effects on preferred conformations of these particular compounds in solution are of secondary importance, the effect of a group on affinity will be the net result of what it could contribute to binding, offset by the disturbance it causes to existing binding. The maximum effect observed in a large number of comparisons may indicate the contribution in the absence of disturbance and for groups containing only carbon and hydrogen it appears to be related to size, assessed from the increments in apparent molal volume at infinite dilution. The variation in the effects of these groups also appears to be related to size. Changes involving groups containing oxygen can produce bigger contributions to binding, and a bigger variation in contribution, than would be expected from their size.6 It is difficult to predict the extent to which groups may fail to produce their maximum effects. Variation is greatest with groups which could produce the biggest changes and so are of the greatest interest.7 The relevance of the results to the successful prediction of biological activity is discussed.