The Use of Drug Antagonists for the Identification and Classification of Drugs

Abstract

A sensitive biological method for the identification of drugs has been described by Chang and Gaddum (1933). It consists in estimating the activity of an unknown substance in terms of a standard, quantitatively, in several different pharmacological tests. As a rule the ratio of activity between standard and unknown in different tests is only constant if the two samples are chemically identical, otherwise the ratio of activity in different tests varies. By this method even closely related substances may be differentiated.Another biological method for the identification and differentiation of drugs consists in testing quantitatively their responses towards antagonists. It has been shown in a previous communication (Schild, 1947) that the effects of histamine and acetylcholine may be thus distinguished, since many antagonists although unspecific at high concentrations will differentiate between these drugs at lower concentrations. The present investigation is concerned with the question whether drugs which are more closely related than histamine and acetylcholine may also be differentiated in this way, or whether antagonists, even though they may be used in an exact and quantitative manner, would fail to discriminate between closely related substances.If indeed some drugs, although distinguishable chemically or by their relative activity in different pharmacological tests, could not be distinguished by their reactions to antagonists, they might conveniently be grouped into a common pharmacological class. It will be shown that drugs can in fact be found which are. related in this way, and that if a certain simple scheme of drug action be accepted a rational classification of active drugs based on their responses to drug antagonists may be attempted. METHODSThe experiments were done on the isolated ileum of the guinea-pig, employing the apparatus for assaying antagonists on isolated tissues which has previously been described (Schild, 1947).

Quantitative studies on the antagonism by naloxone of some narcotic and narcotic‐antagonist analgesics

“…Schild (1947a) has suggested the determination of pA, values as a convenient and quantitative measure of drug antagonism. In subsequent papers (Schild, 1947b;Arunlakshana & Schild, 1959) the identification of agonists which act on the same receptor population was described. Although this method has usually been applied in vitro, several studies were reported recently in which the equivalent of pA2 values were determined in vivo (Cox & Weinstock, 1964;Green & Fleming, 1967;Blane, Boura, Fitzgerald & Lister, 1967;Takemori, Kupferberg & Miller, 1969).…”

Receptor Interactions of Imidazolines: Α‐adrenoceptors of Rat and Rabbit Aortae Differentiated by Relative Potencies, Affinities and Efficacies of Imidazoline Agonists

“…One major difference we have observed between the rat and rabbit aortae is that in rabbit aorta, oxymetazoline is approximately 7 times more potent than noradrenaline whereas in rat aorta, oxymetazoline is approximately 13 fold less potent than noradrenaline (Table 1). This difference in potency of oxymetazoline relative to norad- (Schild, 1947;Furchgott, 1972). This method avoids the problems associated with comparing ED50 values among compounds with differing efficacies.…”

Potentiation of the Response to Histamine by Picolylamines

“…It seems worth recalling that, in contrast to histaminase, the tissue receptors for histamine do not distinguish sharply between primary and secondary amines: the analogue of histamine with a methyl group replacing one of the hydrogens of the terminal amino group is pharmacologically fully active, like histamine (Vartiainen, 1935;Schild, 1947), but it is immune from attack by histaminase.…”