Quantitative Studies of Antagonists for 5‐hydroxytryptamine

Abstract

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.

Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO‐K1 cells expressing human angiotensin II AT1 receptors

“…Most antagonists produce parallel rightward shifts of the angiotensin II concentration-response curve, without a ecting the maximal response. These are classi®ed as surmountable antagonists (Gaddum et al, 1955) and losartan is a typical example (Mochizuki et al, 1995). Insurmountable antagonists are able to depress the maximal response.…”

The Antagonism Between 5‐hydroxytryptamine and Certain Derivatives of Lysergic Acid

“…It has been suggested that an important action of 5-HT may be to modify the responses of tissues to other active substances. The effects on the rabbit's ear of 5-HT combined with various other drugs have been studied by Gaddum and Hameed (1954). The experiments described below are an extension of this work.…”

“…Gaddum and Hameed (1954), and the cause of this discrepancy is unknown, but clear evidence of antagonism has now been consistently obtained in 6 experiments. It is possible that the preparation of ergometrine used by Gaddum and Hameed had become inactive.…”

“…With these higher concentrations the antagonism was unsurmountable (Gaddum, Hameed, Hathway, and Stephens, 1955), so that even large doses of 5-HT had no action. LSD itself causes vasoconstriction (Ginzel and Kottegoda, 1953), which was sufficient to interfere seriously with the experiment when 100 ,ug./l.…”

“…1). Ginzel and Kottegoda (1953) (Gaddum and Hameed, 1954). When higher concentrations (20-100 Mg./1.)…”