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

Abstract

MONTREAL, CANADAHE IMPORTANCE OF PHENANTHRENE derivatives in pharmacology and physiology II is clearly shown by the fact that so many useful drugs and essential metabolites -1L belong to this group. Morphine, codeine, colchioine, the bile acids, the digitalis aglucons, the toad poisons, many carcinogenic hydrocarbons, the vitamin D group, cholesterol and the steroid hormones all possess the phenanthrene or perhydro' phenanthrene nucleus. Up to the present comparatively little attention has been given to the correlations which exist between the chemical structure and the phar' macological actions of the cyclopentano'perhydro'phenanthrene derivatives, and hence it was decided to make a systematic study of this field since an understanding of these correlations is a necessary prerequisite for any planned attempt to synthesize more potent compounds than are now available. Such an investigation was particu' larly tempting because the very important steroid hormones and their metabolites be' long to this group. The recently discovered fact (137) that hormonally active steroids, if administered intraperitoneally or intravenously, produce anesthesia in the rat, sup' plies us with a simple test revealing pharmacological activity among such compounds.In the present communication we should like to summarize the most outstanding re' suits of these investigations, which were possible only through the full'hearted CO' operation of numerous outstanding steroid chemists of many countries, who furnished us with the necessary compounds. 2 Although the main object of our study was to correlate chemical structure with the anesthetic effect of the steroids, in some cases special assays were performed to ex' amine the compounds for other hormonal actions. EXPERIMENTAL METHODSSince it was found that the anesthetic effect of the steroids is increased by partial extirpation of the liver (138), apparently because they are normally detoxified in this organ, we performed our assays in the partially hepatectomized rat. In order to facilitate a comparative study, it appeared desirable to establish a R.U. of anesthetic effect. This anesthetic rat unit (A.R.U.) is defined as the minimum amount of a steroid which, when injected intraperitoneally, causes loss of the righting reflex in 4 of 6 female rats

Nongenomic Steroid Action: Controversies, Questions, and Answers

“…In 1942, Hans Selye published a study on the correlation between chemical structure of steroids and their pharmacological action (437). In this study, rats were administered a number of different steroids intraperitoneally, and very rapid anesthetic effects were noticed.…”

Progestins influence motivation, reward, conditioning, stress, and/or response to drugs of abuse

“…Progestins can act as a discriminative stimulus in rats perhaps related to their profound anesthetic effects (Selye, 1942). P (100 mg/kg, IP, 15-30 min before the test) and a synthetic hypnotic (viadril 25 mg/kg) exert similar discriminative stimulus effects in the T-maze (De Beun, 1999;Stewart et al, 1967).…”

Progesterone metabolites in breast cancer

“…Some of the same P metabolites had been identified as active regulatory molecules in other tissues and with respect to other processes. For example, 5a-pregnanes such as 5aP (Selye 1942), 5a-pregnan-3a-ol-20-one (Majewska et al 1986, Kavaliers & Wiebe 1987, and 3aHP (Wiebe & Kavaliers 1988) elicited marked anesthetic or analgesic effects via mechanisms involving calcium channels, the g-aminobutyric acid(GABA)-benzodiazepine-chloride complex and endogenous opioid systems. 20aHP elevated serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in rats (Gilles & Karavolas 1981), whereas 3aHP selectively suppressed basal and LH-releasing hormonestimulated FSH secretion from primary cultures of anterior pituitary cells (Wood & Wiebe 1989) by nongenomic mechanisms at the level of the gonadotrope membrane, protein kinase C cell signaling pathway, and intracellular Ca 2C mobilization (Dhanvantari & Wiebe Endocrine-Related Cancer (2006) 13 717-738…”