IN a previous paper [Gaddum and Hameed, 1954] we have summarized earlier work on antagonists for 5-hydroxytryptamine (HT) and described experiments with known drugs. The present paper gives the results of a study of the actions of a number of indole compounds in order to discover active antagonists. It was necessary to measure their potencies, and our attention was thus drawn to some of the difficulties which arise when antagonists are compared quantitatively with one another.Rough measurements may be made by finding the dose necessary to abolish the effect of the active drug (the "agonist") completely. Such measurements are unlikely to be very accurate since the result will depend on the dose used, and on the sensitivity of the record to small effects produced in the presence of the antagonist. Our own experience of this type of experiment confirms the impression that it is not very reliable. It is probably more satisfactory to use a method depending in some way on a measurement of the effect produced by the antagonist, and it is with such methods that this paper is mainly concerned.When the effect of a given dose of agonist is inhibited, it is generally found that larger doses are still effective, but can be blocked by larger doses of the antagonist. Such results are sometimes described by calling the antagonism competitive, but simple experiments of this type do not prove the theory that the two drugs are competing with one another for the same receptor in the tissue. Some other word is needed to describe the observation that an increase of dose of either drug overcomes the effect of the other. It is proposed to call antagonisms of this type surmountable, and to include in this group the antagonisms which have been called competitive, non-competitive and uncompetitive [Chen and Russell, 1950], as well as those which depend on the two drugs combining with one another to form an inactive complex [Gaddum, 1943]. Examples of unsurmountable antagonisms will be discussed later.

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1. A single oral dose of [(14)C]Ionox 100 to rats is almost entirely eliminated in 11 days: 89.1-107.2% of the (14)C is excreted and 0.29+/-0.02% of the dose is present in the carcass plus viscera after removal of the gut. Rats exhibit an individual variation in the elimination pattern, 15.6-70.8% of (14)C being excreted in the urine and 75.2-27.0% in the faeces during 11 days. 2. After the oral administration of [(14)C]Ionox 100 to dogs, 87.1-90.3% of the (14)C is excreted in the faeces and urine during 4 days. 3. Dogs and rats do not show a species difference in this pattern of elimination. 4. The rate of elimination from dogs and rats given a single dose of Ionox 100 is not affected by the size of the dose and the presence of triglyceride fat in the diet. 5. Ionox 100 is completely metabolized in dogs and rats: unchanged Ionox 100 is absent from the urine and faeces, and from the carcass when elimination is complete. In rats, 3,5-di-tert.-butyl-4-hydroxybenzoic acid accounts for 50-85% of a dose of Ionox 100 and (3,5-di-tert.-butyl-4-hydroxybenzoyl beta-d-glucopyranosid)uronic acid for 47-10%; in dogs, the unconjugated acid accounts for 85% and the ester glucuronide for 10-12%. 3,5-Di-tert.-butyl-4-hydroxyhippuric acid is not formed. Other metabolites, which have been detected in small quantity in the faeces and urine of animals dosed with Ionox 100, have not been identified. 6. 3,5-Di-tert.-butyl-4-hydroxybenzoic acid and (3,5-di-tert.-butyl-4-hydroxybenzoyl beta-d-glucopyranosid)uronic acid are also the major metabolites of Ionol (2,6-di-tert.-butyl-p-cresol) in rats. 7. The elimination of Ionox 100 metabolites from rats is faster than that of Ionol and its metabolites. Unlike Ionol, unchanged Ionox 100 could not be detected in the bodies of these animals.