General Structure‐Activity Correlations of Antihormones

Teutsch, G.; Nique, F.; Lemoine, G; Bouchoux, F.; Cerede, E.; Gofflo, Dominique; Philibert, D.

doi:10.1111/j.1749-6632.1995.tb31365.x

Cited by 19 publications

(9 citation statements)

References 65 publications

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“…However, residues in block g4 (644-KH) and g6 (653-LHR) were also involved in discriminating between the two glucocorticoid ligands. Note that all the chimeric receptors studied were able to bind RU 38486, but did not always bind RU 43044 ( Table 3), suggesting that the region accommodating the 11␤ moiety (RU 38486) was conserved throughout the chimeric receptors studied, unlike the one responsible for 19-aryl moiety (RU 43044) binding (16). This is in agreement with results indicating that Gly722 of hPR is the only major requirement for RU 38486 binding to steroid receptor.…”

Section: Ligand Discrimination and Transactivation Modulation By Leu647supporting

confidence: 90%

Residues in the Ligand Binding Domain That Confer Progestin or Glucocorticoid Specificity and Modulate the Receptor Transactivation Capacity

Robin-Jagerschmidt¹,

Wurtz

Guillot

et al. 2000

Molecular Endocrinology

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To localize regions conferring ligand binding specificity of the human glucocorticoid (hGR) and progesterone (hPR) receptors, we constructed chimeras comprising the DNA-binding domain of the yeast transcription factor GAL4, linked to the ligand binding domain of hGR or hPR. Replacement of a sequence of hGR encompassing helices H6 and H7 with the homologous sequence from hPR creates a chimeric protein GP3, which binds the progestin RU 27987 with high affinity, and results in a concomitant loss of glucocorticoid binding [dexamethasone (DEX), RU 43044]. Moreover, GP3 is not able to mediate RU 27987-induced transactivation. A detailed mutational analysis of this sequence and the study of the recently solved hPR crystal structure revealed five residues that confer progestin responsiveness to GR or modulate ligand binding and transcriptional activation. Notably, the simultaneous presence of residues Ser637 and Phe639 on GP3, lining the ligand binding pocket, is specifically involved in RU 27987 binding. The absence of residues Asp641, Gln642, and Leu647 on GP3 is accountable for the lack of glucocorticoids binding on GP3. Unlike residue 642, residues 641 and 647 are not in direct contact with the ligand and most likely act through steric-mediated interactions. The presence of Gln642 and Leu647 are determinant for transcriptional activation in response to DEX and RU 27987, respectively. DEX-dependent transactivation is further enhanced by the presence of Leu647.

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Section: Ligand Discrimination and Transactivation Modulation By Leu647supporting

confidence: 90%

Residues in the Ligand Binding Domain That Confer Progestin or Glucocorticoid Specificity and Modulate the Receptor Transactivation Capacity

Robin-Jagerschmidt¹,

Wurtz

Guillot

et al. 2000

Molecular Endocrinology

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“…However, there is no reason why all ligands should be positioned in the same way or in exactly the same binding pocket. It is more likely that we have to deal with a more subtle repositioning, taking into account several factors in addition to the functional groups, e.g., length of the molecule, conformational rigidity, and overall flatness (Burton et al, 1995;Teutsch et al, 1995). In this sense, note that 11-OP lacks a C 21 -hydroxyl, a group that was always thought to be essential for the biological activity.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Action of the Potent Sodium-Retaining Steroid 11,19-Oxidoprogesterone

et al. 2000

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We have demonstrated previously that a planar conformation of the molecular frame is required for steroids to acquire optimal sodium-retaining activity and binding properties to the mineralocorticoid receptor (MR). One of the most active sodiumretaining compounds tested in those studies was 11,19-oxidoprogesterone. Despite its biological potency, the relative affinity of 11,19-oxidoprogesterone for the MR is 5-fold lower than that of 21-deoxycorticosterone and 10-fold lower than aldosterone. Such a discrepancy may be assigned to uncommon biopharmacological properties of this synthetic steroid or an unusual molecular mechanism of action. In this work, we studied the biopharmacological and mechanistic features of 11,19-oxidoprogesterone. We show that both the pharmacokinetic properties of 11,19-oxidoprogesterone and its ability to transform and translocate the MR into the nucleus are undistinguishable from aldosterone. However, the capability of the serine/threonine phosphatase inhibitor tautomycin to impair nuclear translocation of the aldosterone-MR complex is not observed for the 11,19-oxidoprogesterone-MR complex. In addition, the binding properties of both steroids are differentially affected by modification of crucial lysyl residues of the MR. Kinetic studies performed on the aldosterone-MR complex in the presence of low concentrations of oxidopregnane suggest that 11,19-oxidoprogesterone may bind to the MR in a different binding site from the aldosterone binding pocket. Consistent with this postulate, a biologically inactive dose of 0.6 ng of oxidopregnane is able to potentiate the mineralocorticoid effect of a suboptimal dose of aldosterone.In contrast to glucocorticoids, which exhibit a slightly torsioned steroid nucleus at the A/B-ring junction, mineralocorticoids seem to require a flat conformation for optimal activity (Duax et al., 1978;Lantos et al., 1981;Yamakawa et al., 1986;Burton et al., 1995). Consistent with this structural requirement, we have reported previously (Burton et al., 1995) that the highly planar synthetic steroid 11,19-oxidoprogesterone (11-OP; see structure in Fig. 1) exhibits potent sodium-retaining activity. In this sense, 11-OP is equivalent to the biological activity measured with 21-deoxycorticosterone (DOC) and, at some doses, even approaches the effects of aldosterone (ALDO). On the other hand, 11-OP differs from endogenous mineralocorticoids in its relatively lower affinity for mineralocorticoid receptor (MR), which is ϳ50 nM as compared with 4 nM for ALDO and 10 nM for DOC.In contrast to the natural mineralocorticoids ALDO and DOC, the synthetic steroid 11-OP lacks a C 21 -hydroxyl group. Also, 11-OP does not possess a functional C 18 -methyl group as found on ALDO and the strong synthetic mineralocorticoid 18-vinylprogesterone. Nevertheless, the overall flat 11-OP is a strong sodium-retaining steroid. In contrast, its highly bent isomer 6,19-oxidoprogesterone (6-OP) exhibits negligible, if any, mineralocorticoid activity. These interesting features suggest that a ...

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“…Microinfusions of the GR antagonist into the NTS did not completely block the effect of dexamethasone, as the highest dose of dexamethasone induced memory enhancement. As RU 38486 is a competitive antagonist (Teutsch et al . 1995), this shift in the dose–response relationship is likely to be due to a competition between dexamethasone and the GR antagonist at receptor sites in the NTS.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: involvement of the basolateral amygdala

Roozendaal

Williams

McGaugh

1999

Eur J of Neuroscience

125

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These experiments examined the involvement of glucocorticoid receptors (GRs or type II) located in the A2-noradrenergic cell group of the rat nucleus of the solitary tract (NTS) in modulating memory storage. Bilateral intra-NTS infusions (0.5 microL) of the specific GR agonist RU 28362 (11beta, 17beta-dihydroxy-6, 21-dimethyl-17alpha-pregna-4,6-trien-20yn-3-one), in doses ranging from 0.01 to 10.0 ng, immediately after inhibitory avoidance training produced a dose-dependent enhancement of 48 h retention performance. Infusions of 0.1 or 1.0 ng of the agonist enhanced retention, whereas lower or higher doses were ineffective. Post-training infusions of the GR antagonist RU 38486 [17beta-hydroxy-11beta-(4-dimethylaminophenyl)-17alpha-(1-pr opynyl)-o estra-4,9-dien-3-one, 0.01-10.0 ng] into the NTS did not significantly affect retention performance, but shifted the dose-response effects of post-training systemic injections of the synthetic glucocorticoid dexamethasone to the right. These results indicate that activation of GRs in the NTS can influence memory formation for inhibitory avoidance training, and suggest that the effects of circulating glucocorticoids on memory are mediated, in part, by an activation of GRs in the NTS. Additionally, pretraining infusions of the beta1-adrenergic antagonist atenolol (0.5 microg in 0.2 microL) into the basolateral nucleus of the amygdala (BLA), a brain structure which receives noradrenergic projections from the NTS and is implicated in memory storage modulation, blocked the memory-enhancing effects of the GR agonist (1.0 ng) infused into the NTS. These findings provide evidence that memory storage is modulated by glucocorticoid binding to GRs in noradrenergic cell bodies in the NTS and suggest that these modulatory effects are conveyed by ascending projections to the BLA.

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General Structure‐Activity Correlations of Antihormones

Cited by 19 publications

References 65 publications

Residues in the Ligand Binding Domain That Confer Progestin or Glucocorticoid Specificity and Modulate the Receptor Transactivation Capacity

Residues in the Ligand Binding Domain That Confer Progestin or Glucocorticoid Specificity and Modulate the Receptor Transactivation Capacity

Mechanism of Action of the Potent Sodium-Retaining Steroid 11,19-Oxidoprogesterone

Glucocorticoid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: involvement of the basolateral amygdala

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