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Glucocorticoid Antagonists View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Volume 217, number 2, 221-226 FEB 04855 June 1987 Review Letter Glucocorticoid antagonists M.K. Agarwal*, B. Hainque+, N. Moustaid” and G. Lazert UER Broussais Hotel-Dieu, Centre Universitaire des Corakliers, 15 rue de 1’Ecole de Medecine, 75270 Paris Cedex 06, France Received 28 April 1987 1. BACKGROUND 2. STRUCTURE-AFFINITY CONSIDERATIONS The three principal areas of application of hor- mone antagonists are: clinical, diagnostic, and Two types of structural modifications of the delineation of hormone action ([l-5] for reviews). steroid molecule have been attempted, namely in Inhibition of synthesis of glucocorticoids in the the C and the D rings. It is clear that an alcohol adrenal cortex was attempted nearly three decades function in the 1 I,&position is required for agonist ago using metyrapone and aminogluthemide activity. The 1 la-hydroxycortisol, the 11-keto derivatives [3,5], and more recently with an- derivative (cortisone), and the 1 1-deoxy analogue timycotic agents [6,7]. Some 45 years ago an- (cortexolone) of cortisol are antagonists in various drogens and superandrogens R 2999 and R 4841 systems in vitro [2,3,8]. Some 20 years ago, cortex- [8-l 11, progesterone [12,13], oestrogens [8,14], olone was the only antiglucocorticoid effective on and insulin [2] were used to oppose clinical effects both the liver and thymus in vivo in adrenalec- of glucocorticoids, despite numerous side effects. tomised animals [2,3,8], but was transformed into Physiological actions of corticoids in animals an agonist after hydroxylation in the lip position could also be antagonized [ 1% 191 but the response in the adrenals of intact animals [l-3]. The 11-oxa was equivocal [ 111. derivatives of both cortisol and prednisolone It is generally admitted that adrenocorticoid (fig.1) cannot be hydroxylated in the 11 position hormone action proceeds via a soluble, and retained the antagonist activity in vivo [20]. cytoplasmic receptor in the target cell [l-5]. Thus, The receptor binding correlated with biological ac- an ‘ideal’, specific, antagonist, devoid of side ef- tivity in these studies. fects, would have to be sought by structural Another school of thought lays greater emphasis modification of the native hormone in relation to on modifications in the D ring of the steroid for the receptor structure. genesis of antagonists than on the C ring [3,5]. The 17-21 acetonides of cortisol and cortexolone are only marginally active derivatives [21] and 17-21 Correspondence address: M.K. Agarwal, 15 rue de oxetanones of cortisol and dexamethasone are only 1’Ecole de Medecine, 75270 Paris Cedex 06, France weak antagonists of enzyme induction in * Directeur de Recherche, CNRS hepatoma cells in vitro [20]. + Charge de Recherche, INSERM D ring substitution led to the synthesis of o Doctoral student mesylates of cortisol and dexamethasone (fig. 1) + Recipient of INSERM International Fellowship that form affinity labels by an irreversible Published by Elsevier Science Publishers B. V. (Biomedical Division) 00145793/87/$3.50 0 1987 Federation of European Biochemical Societies 221 Volume 217, number 2 FEBS LETTERS June 1987 0 0 : -CH2 -OH 'c--Hz--H OH OH 0+ 0" II-OXA CORTISOL II-OXA PREDNISOLONE CORTISOL OXETANONE DEXAMETHASONE OXETANONE CORTISOL MESYLATE DEXAMETHASONE MESYLATE CORTISOL ACETONIDE CORTEXOLONE ACETONIDE C - CH2 - OH OH CORTEXOLONE RU 38486 (MIFEPRISTONEI Fig. 1. Structural formulae of some leading antiglucocorticoids. blockade of the cytosolic receptor [20]. They are involves a modification in both the 11 position and only partial antagonists in vitro and very toxic in the ketolic side chain [22,23]. A large number of vivo [20]. The 17@-carboxamides antagonised en- derivatives has been synthesized starting from zyme induction in hepatoma cells, but were ap- RU 26988, the ideal glucocorticoid agonist. These parently destined to oblivion since then [21]. were subsequently used as potent probes to map the steroid-binding domain (SBD) on the receptor, and to prove the determining role of the 11 posi- 3. THE EPOXIDE PATHWAY tion in the agonist vs the antagonist action, The discovery of the epoxide pathway at Roussel although the A ring is believed to be important in laboratories [3,5] opened up a whole new area in binding to the receptor [3,4]. the antiglucocorticoid field. The chemical reaction Thus, all 1 l,&aryl derivatives are devoid of pro- 222 Volume 217, number 2 FEBS LETTERS June 1987 gesterone receptor (PR) binding activity whereas mineralocorticoid receptor could be activated just the vinyl derivative has strong affinity for PR and as well in the presence of the agonist aldosterone as is also a full glucocorticoid receptor (GR) agonist with the antagonist RU 26752 [35]. Thus, receptor [4,5,8,24]. Substitution in the para position has a activation is not an exclusive property of hormonal moderate effect on the SBD but meta substitution steroids, contrary to earlier studies [l-5]. decreases affinity for PR leading to some dissocia- Nuclear translocation of GR bound to tion between binding to the two types of receptors. Mifepristone was impaired in isolated rat thymus Finally, the introduction of a bulky residue in the nuclei in vitro whereas agonist-GR was avidly p-diphenyl configuration does not reduce binding bound to nuclei [30]. Similarly, murine thymoma to either GR or PR, suggesting that both these Mifepristone-GR complexes exhibited diminished receptors contained a hydrophobic pocket binding to murine mammary tumour virus DNA [3,5,22,23]. Actually, it is the size of this substi- promoter as compared to the agonist-GR com- tuent which determines the agonist vs the an- plexes [36]. These results cast doubt on the in- tagonist activity, since the synthesis of the tranuclear localization of Mifepristone by 1 l&(4-dimethylaminophenyl) derivative led to the autoradiography [37] where chemical analysis of discovery of the most potent antisteroid for both the nuclear bound radioactivity was required to the glucocorticoid and the progesterone series rule out rapid metabolic conversions in vivo [38]. [3,5,8,22,23]. What follows is essentially a Thus, intranuclear events seem more important catalogue of the success story of this newly syn- than those in the cytosol for the physiological ac- thesized derivative dubbed RU 38486, or simply tion of Mifepristone. RU 486, now named Mifepristone (1 l&(4-di- Recently, a 90 kDa protein was found to be a methylaminophenyl)- 17,&hydroxy- 17a-(propyl- l- common component of both the GR and the PR ynyl)estra-4,9-dien-3-one). [39] which recalls a similar hydrophobic pocket in the steroid-binding domain of the receptor for these two classes of hormones [3,5,8,24]. Contrary 4. A NEW RECEPTOR PROBE to the current notion, rat liver GR-Mifepristone In view of receptor heterogeneity [24,25], which complexes did not bind to the idiotype antibody is not due to receptor fragmentation by en- obtained in the rabbit with TA-BSA, implying dif- dogenous proteases [26-281, it was important to ferences in the conformation and topology of the establish whether the agonists would saturate the active site [40]. Chick oviduct, too, exhibited two same receptor populations as the antagonists. separate binding sites, one each for progesterone Mifepristone was bound to the same population of and Mifepristone, contrary to the situation in calf GR as various agonists in hepatoma cells [ 121, uterus where both materials saturated an identical thymocytes [29-311, and rat liver [32,33]. receptor [34]. Mifepristone did not bind to The affinity of Mifepristone was found to be less transcortin and was a better ligand than dex- than that of the agonist triamcinolone acetonide amethasone for chick oviduct GR [41]. All these (TA) for rat liver GR [33] but higher than that of results largely confirm some of our earliest studies dexamethasone for GR in rat thymus [3,30,31] and on receptor multiplicity [25,26]. in hepatoma cells [ 12,311. The rate of dissociation of Mifepristone from the activated GR was much 5. CELLULAR ACTION OF MIFEPRISTONE faster than with the agonist in thymus [29-311, as well as rat liver [33], cytosol and this was partially The anabolic action (increased RNA, protein prevented by molybdate and phosphate buffers synthesis, enzyme induction, gluconeogenesis) of [29]. Paradoxically, Mifepristone-bound PR gave glucocorticoids in the liver is to be contrasted with more stable complexes at 35°C than those obtained their catabolic action (decreased macromolecular with progesterone in chick oviduct cytosol [34]. synthesis, fragmentation, cell death) in lymphatic Whereas rat liver GR-Mifepristone complexes tissues such as the thymus (reviews in [l-4]). could be heat-activated just as well as TA-GR com- In adrenalectomised rats, Mifepristone abol- plexes [33], rat thymocyte GR could be activated ished the induction of tryptophan pyrrolase (TP) only partially [30]. Recently, rat kidney and tyrosine transaminase (TT), as well as 223 Volume 217, number 2 FEBSLETTERS June 1987 gluconeogenesis, in response to synthetic glucocor- which is reversed by Mifepristone [52]. On the ticoids [3,32]. More important, the basal level of other hand, glucocorticoids can induce hyperten- these parameters ,was not influenced in control sion in the rat and this can also be antagonised by animals given Mifepristone alone. Increase in TP Mifepristone which exhibits no intrinsic activity of levels, seen as a result of endogenous cor- its own [53]. Finally, hydrocortisone was shown to ticosterone secretion following ethanol administra- increase angiotensinogen synthesis in Reuber tion, was also reversed by Mifepristone [42]. hepatoma cells in vitro and this too could be Although cultured hepatoma cells are much in prevented by Mifepristone [54]. These data suggest use, neoplastic transformation permits the expres- that glucocorticoids may be involved in the regula- sion of only the TT gene [l-4].
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