CORRELATIONS BETWEEN THE CHEMICAL STRUCTURE AND THE PHARMACOLOGICAL ACTIONS OF THE STEROIDS1

Abstract

75 steroid compounds were studied for their anesthetic effect in the rat. Additional bioassays for various hormonal activities were also performed. These investigations led to the following conclusions. A distinction must be made between the subordinated and the independent actions of the steroids. The former are merely side effects of another pharmacological action with which they are invariably associated, as for instance the prostate-stimulating action of steroids is subordinated to their general testoid activity. However, 6 of the steroid hormone actions may be regarded as independent of each other. These are the folliculoid, corticoid, luteoid, testoid, gonadotrophic and anesthetic effects. Certain pharmacological actions, especially the anesthetic and vagina-stimulating effects, are common to the great majority if not to all steroids having no side chain or one which consists of no more than 2 carbon atoms. The highest anesthetic effect is exhibited by steroids oxygenated only at the 2 extreme ends of the molecule. One double bond does not appear to interfere seriously with the anesthetic effect if it is situated in ring A or B, but 2 or more double bonds in these 2 rings or 1 double bond in ring D is detrimental. Esterification decreases the anesthetic effect if it delays absorption, while the reverse is true in the case of particularly readily soluble esters. The steric position of the hydroxyl group in position C3 is apparently without importance for the anesthetic effect, at least in the androstane and etiocholane series. A 5-membered ring D is not indispensable either for the anesthetic or the folliculoid effect, as shown by the 2 chrysopregnene derivatives in this series. Contrary to common belief, an [alpha]-[beta]-un-saturated ketone group in positionC3 is not essential for corticoid activity. The same molecule may be endowed with 2 antagonistic pharmacological properties which can be demonstrated by the use of different test objects (for example, pregnenolone is folliculoid in the spayed rat inasmuch as it causes vaginal cornification, yet it antagonizes the testis-atrophy-producing effect of estradiol, another folliculoid compound). The presence of a hydrogen at C5, in a position cis to the C10 methyl group (etiocholanes and 17-alkyl-etiocholanes), is incompatible with any definite, known hormone activity but may be associated with high anesthetic potency.