No abstract

No abstract

No abstract

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 drugs which act as antagonists of 5-hydroxytryptamine (5-HT) give different results when tested on different preparations. Various derivatives of ergot have been found to be very potent antagonists of 5-HT in experiments on the rat uterus or on the rabbit ear perfused with salt solutions, but the ergot derivatives were not, however, very potent antagonists of 5-HT in the case of the guinea-pig ileum (Fingl and Gaddum, 1953; Gaddum, 1953; Gaddum and Hameed, 1954; Gaddum, Hameed, Hathway, and Stephens, 1955).In order to explain such facts, Gaddum and Hameed (1954) suggested the existence of two kinds of tryptamine receptor: one in the plain muscle of the rat uterus and the rabbit ear which was easily blocked by lysergic acid diethylamide (LSD), gramine, or dihydroergotamine, and another in the intestine, not easily blocked by such drugs.There is evidence that 5-HT causes contraction of the guinea-pig intestine by acting through the nerves, but this is not due to an action on the nicotine receptors, since it is not suppressed by hexamethonium or by the eventual paralytic action of large doses of nicotine (Rocha e Silva, Valle and Picarelli, 1953; Robertson, 1953 (180-250 g.) which had fasted overnight, and suspended in a 2 ml. bath containing aerated Tyrode solution maintained at 35'. The movements of the longitudinal muscle were recorded with a frontal lever having a magnification of xS.Effects of Antagonists.-The effects of the antagonists have been measured in terms of the dose-ratio (Gaddum et al., 1955) by constructing dose-effect curves for the stimulant drugs at the beginning of the experiment, and comparing their subsequent effects in the presence of the antagonist with these curves. The dose-ratio is the ratio of equiactive doses in the presence and absence of the antagonist.The concentration of the various antagonists was maintained in the bath either by adding fresh doses

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.