Synthesis of new 11.beta.-substituted spirolactone derivatives. Relationship with affinity for mineralocorticoid and glucocorticoid receptors

Abstract

Various steroidal 17-spirolactones substituted in the 11 beta-position were synthesized to study the relationship between the nature of the 11 beta-arm and their affinity for cytosolic mineralocorticoid (MR) and glucocorticoid (GR) receptors prepared from adrenalectomized rabbit kidney or liver. One of them, the 11 beta-allenyl-3-oxo-19-nor-17-pregna-4,9-diene-21,17- carbolactone derivative, exhibited the same affinity for MR as aldosterone and a 5-fold higher affinity than mespirenone. Its affinity for GR was found to be relatively low. As suggested by molecular modeling, the marked differences in mineralocorticoid receptor binding affinity could be related to the structural features induced by this 11 beta-allenic substituent.

A Single Amino Acid Mutation of Ala-773 in the Mineralocorticoid Receptor Confers Agonist Properties to 11β-Substituted Spirolactones

“…Aldosterone and progesterone were obtained from Sigma (St. Louis, MO), RU26752 from Roussel Uclaf Laboratories (Romainville, France) and spironolactone (SC9420) was from Searle Laboratories (Chicago, IL). 11␤-Vinyl-3-oxo-19-nor-17␣-pregna-4,9-diene-21,17-carbolactone (1), 11␤-allenyl-3-oxo-19-nor-17␣-pregna-4,9-diene-21,17-carbolactone (2), 11␤-(3-hydroxypropyl)-3-oxo-19-nor-17␣-pregna-4,9-diene-21,17-carbolactone (3), 11-ethylidene-3-oxo-19-nor-17␣-pregna-4,9-diene-21,17-carbolactone (4), 11-(3-propenylidene)-3-oxo-19-nor-17␣-pregna-4,9-diene-21,17-carbolactone (5), 4,9(10)-androstadiene-3,17-dione (6), and 11␤-allenyl-3-oxo-19-nor-17␣-pregna-4,9-diene-3,17-dione (7) were synthesized according to Faraj and Claire (Faraj et al, 1990;Claire et al, 1993). Structure and abbreviations of the steroids are given in Fig.…”

“…Its ability to bind SRC-1, a coactivator known to interact with several members of the NR superfamily (Onate et al, 1995;Jenster et al, 1997;Shibata et al, 1997), was also tested and its transactivation activity was measured by cotransfection assays. The compounds tested were synthesized in our laboratory (Faraj et al, 1990;Claire et al, 1993); they differ at the C11-and/or C17-positions (Fig. 2).…”

Mineralocorticoid receptor mediates glucocorticoid treatment effects in the autoimmune mouse ear

“…Steroid-mediated hearing improvement has traditionally been attributed to the anti-inflammatory and immunosuppressive activities of glucocorticoids, but they also are effective in cases of sudden and rapidly progressing hearing loss with no demonstrable immunologic problem. Glucocorticoids actually have a high binding affinity to the mineralocorticoid receptor (Claire et al, 1993;Rupprecht et al, 1993;Munck et al, 1990;Arriza et al, 1987) and this potential impact on ion homeostasis in the ear has largely been ignored in explaining steroid-responsive ear disease. If hearing loss is due to disruption of stria vascularis functions, the efficacy of glucocorticoids may be due to their restoration of normal endolymph ion balances.…”

Blocking the Glucocorticoid Receptor with RU-486 Does Not Prevent Glucocorticoid Control of Autoimmune Mouse Hearing Loss

“…Both mineralocorticoid [40,41] and glucocorticoid [42,43] receptors occur in the ear, and recent studies of cochlear pharmacokinetics of glucocorticoids have begun to clarify some parameters of steroid flow and scalar distribution, particularly after transtympanic delivery [44,45,46,47,48,49]. It is well established that glucocorticoids have an affinity for the mineralocorticoid receptor that is equal to or higher than affinity for the glucocorticoid receptor [50,51,52]. The glucocorticoid immunosuppressive and anti-inflammatory functions are mediated through the glucocorticoid receptor, whereas sodium and potassium exchange is controlled by glucocorticoid activation of the mineralocorticoid receptor [53,54,55,56].…”