The affinity and activity of compounds related to nicotine on the rectus abdominis muscle of the frog (Rana pipiens).

1. Series of pyridylalkyl- and substituted phenylalkyl-trimethylammonium salts, triethylammonium salts, diethylamines and di-n-propylamines have been made. The substituents in the benzene ring were nitro, chloro, bromo, methoxy, hydroxy and amino groups and the alkyl residues had one, two, or three methylene groups separating the aromatic nucleus from the cationic head.2. Most of the trimethylammonium compounds caused a contracture of the frog rectus muscle, but some were partial agonists and a few were antagonists. The di-n-propylamines were all antagonists, as were most of the diethylamines and triethylammonium compounds, though some of these were partial agonists and a few triethylammonium compounds were agonists. The affinities of the antagonists and partial agonists for the receptors stimulated by beta-pyridylmethyltrimethylammonium (and by nicotine) were measured. The equipotent molar ratios of all the agonists were measured relative to beta-pyridylmethyltrimethylammonium.3. The dissociation constants of the pyridylmethyldiethylamines and substituted benzyldiethylamines were measured. The effects of substituents on the pK(a) of benzyldiethylamine were similar to their effects on the pK(a) of aniline, though there were differences with some of the o-substituted compounds, which could be attributed to internal hydrogen-bond formation.4. There is no obvious correlation between the effects of a substituent on the pK(a) of benzyldiethylamine and its effects on affinity. Although increasing the size of the cationic group usually increased affinity, it did not always do so. The compounds with the highest affinity, p-hydroxybenzyldiethylamine (log K, 5.90) had about half the affinity of (+)-tubocurarine (log K, 6.11), but the triethylammonium analogue (log K, 4.17) had only about one-fiftieth of the affinity of the tertiary base. The binding of the drug to the receptor appears to involve many factors which include the size of the groups as well as their electron-releasing or withdrawing nature and other properties, such as their polar and lipophilic or lipophobic character.5. There is no obvious correlation between the effects of a substituent on the affinity of the diethylamino or triethylammonium compounds and its effects on the activity of the trimethylammonium analogue. The most active compounds contain hydroxy- and amino-, phenyl or beta-pyridyl groups, m-hydroxyphenyl-propyltrimethylammonium being about 50 times as active as nicotine, but the corresponding diethylamino or triethylammonium compounds do not have high affinity. There does not seem necessarily to be an inverse relationship between activity and affinity, however, because some m-nitro and m-chloro trimethylammonium compounds have considerable activity and the analogous triethylammonium compounds have considerable affinity.6. It is suggested that ability to activate these receptors is associated with the presence of substituents which can interact with water molecules which may be involved in the action of the drug at the receptor.