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An enzyme, hydroxyindole-O-methyl transferase, that can transfer the methyl group of S-adenosylmethionine to the hydroxy group of N-acetylserotonin to form the hormone melatonin is described. This enzyme, which is highly localized in the pineal gland, also O-methylates serotonin.
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Some 3-(2-dialkylaminoethyl)-, 3-(2-alkylaminoethyl)-, and 3-(2-dialkylaminoethyl)-2-methylindoles have been synthesized and tested, along with 5-benzyloxygramine, 5-benzyloxy-3-(2-dimethylaminoethyl)-, 3-(2-aminopropyl)- and 3-(2-aminobutyl)-indoles, on the rat uterus and rat fundus strip. 5-Benzyloxy-3-(2-dimethylaminoethyl)indole, even though it contains an ethylene side-chain, was a less potent antagonist of 5-hydroxytryptamine than was 5-benzyloxygramine. The remaining compounds were still less active. There are differences between the ability of some of them to antagonize 5-hydroxytryptamine and to antagonize tryptamine. 3-(2-Dimethylaminoethyl)-2-methylindole, in particular, shows a considerable degree of specific antagonism of 5-hydroxytryptamine on both tissues.Nearly all the compounds stimulate the preparations, some combining antagonism of 5-hydroxytryptamine at low concentrations with stimulant activity at higher concentrations. The most active compound is 3-(2-dipropylaminoethyl)indole. On the rat fundus strip this has, on a molar basis, 1/40th of the stimulant activity of 5-hydroxytryptamine, and is 20 times as active as tryptamine: on the rat uterus it is only 1/200th as active as 5-hydroxytryptamine, and equal in activity to tryptamine.
The search for substances which antagonize 5-hydroxytryptamine, and for those which act like it, has been extended to cover 5-substituted indoles which are analogues of 5-hydroxytryptamine, rather than analogues of tryptamine like the compounds previously studied by us. The isolated rat uterus and rat fundus strip preparations have been used to determine activity. The relationships between structure and activity of the compounds studied were not the same on the two preparations nor were they the same from one homologous series to another. These differences may be partly explained by the presence of amine oxidase in the rat fundus, as Vane (1959) has suggested, and by supposing that it is absent from the rat uterus. None of the compounds had marked antagonist activity. The most active antagonist on the rat uterus was 3-(2-aminopropyl)-5-benzyloxyindole, but this was less potent than 5-benzyloxygramine. On the rat fundus strip, however, the only antagonist, 5-benzyloxy-3-(2-dimethylaminoethyl)indole, was more active than 5-benzyloxygramine. On both preparations the most active stimulant was 3-(2-aminopropyl)-5-benzyloxyindole, which was about half as potent as 5-hydroxytryptamine. The next most active were 3-(2-aminopropyl)-5-methoxyindole and bufotenine.
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There are two kinds of tryptamine receptor in the guinea-pig ileum, namely the M receptors which can be blocked with morphine and the D receptors which can be blocked with dibenzyline. Atropine, an atropine-like drug, cocaine, and methadone inhibit effects due to the M receptors, even after dibenzyline, but have no additional effect after morphine. Lysergic acid diethylamide, dihydroergotamine and 5-benzyloxygramine inhibit effects due to the D receptors, even after morphine, but have no additional effect after dibenzyline. The M receptors are probably in the nervous tissue and the D receptors are probably in the muscles.
The relative potencies of analogues of tryptamine and 5-hydroxytryptamine have been determined on the rat fundus preparation. This tissue had an amine oxidase activity, which, in the homogenate, was able to inactivate both tryptamine and 5-hydroxytryptamine to about the same degree. Amine oxidase inhibitors potentiated the action of tryptamine and many analogues on the isolated rat fundus preparation, but not the action of 5-hydroxytryptamine or of other hydroxytryptamines. This suggested that, in the isolated organ, the amine oxidase was unable to inactivate 5-hydroxytryptamine, but could inactivate tryptamine, 5-methoxytryptamine and many others. These results may be explained if it is supposed that tryptamine entered the cell, but because of the polar hydroxyl group 5-hydroxytryptamine did not. This hypothesis is supported by the oil/water partition coefficients. The structure/activity of the various tryptamine derivatives is discussed in the light of this assumption.