title: A Mixed Glucocorticoid/Mineralocorticoid Selective Modulator With Dominant Antagonism in the Male Rat Brain.
abstract: Adrenal glucocorticoid hormones are potent modulators of brain function in the context of acute and chronic stress. Both mineralocorticoid (MRs) and glucocorticoid receptors (GRs) can mediate these effects. We studied the brain effects of a novel ligand, C118335, with high affinity for GRs and modest affinity for MRs. In vitro profiling of receptor-coregulator interactions suggested that the compound is a "selective modulator" type compound for GRs that can have both agonistic and antagonistic effects. Its molecular profile for MRs was highly similar to those of the full antagonists spironolactone and eplerenone. C118335 showed predominantly antagonistic effects on hippocampal mRNA regulation of known glucocorticoid target genes. Likewise, systemic administration of C118335 blocked the GR-mediated posttraining corticosterone-induced enhancement of memory consolidation in an inhibitory avoidance task. Posttraining administration of C118335, however, gave a strong and dose-dependent impairment of memory consolidation that, surprisingly, reflected involvement of MRs and not GRs. Finally, C118335 treatment acutely suppressed the hypothalamus-pituitary-adrenal axis as measured by plasma corticosterone levels. Mixed GR/MR ligands, such as C118335, can be used to unravel the mechanisms of glucocorticoid signaling. The compound is also a prototype of mixed GR/MR ligands that might alleviate the harmful effects of chronic overexposure to endogenous glucocorticoids.
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: Erika
authors: E
authors: Atucha
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: Ioannis
authors: I
authors: Zalachoras
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: José K
authors: JK
authors: van den Heuvel
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: Lisa T C M
authors: LT
authors: van Weert
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: Diana
authors: D
authors: Melchers
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: Isabel M
authors: IM
authors: Mol
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: Joseph K
authors: JK
authors: Belanoff
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: René
authors: R
authors: Houtman
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: Hazel
authors: H
authors: Hunt
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: Benno
authors: B
authors: Roozendaal
authors: Department of Cognitive Neuroscience (E.A., L.T.C.M.v.W., B.R.) Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands; Department of Internal Medicine (I.Z., J.K.v.d.H., L.T.C.M.v.W., I.M.M., O.C.M.), Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, and Leiden Institute for Brain and Cognition, Leiden University Medical Center, 2300 RA Leiden, The Netherlands; PamGene International (D.M., R.H.), 2511 HH Den Bosch, The Netherlands; and Corcept Therapeutics (J.K.B., H.H.), Menlo Park, California 94025.
authors: Onno C
authors: OC
authors: Meijer
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics; D008024:Ligands; D008297:Male; D008568:Memory / Q000187:drug effects; D000451:Mineralocorticoid Receptor Antagonists / Q000378:metabolism* / Q000494:pharmacology; D008901:Mineralocorticoids / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D013941:Thymine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003345:Corticosterone; D003907:Dexamethasone; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D008024:Ligands; D000451:Mineralocorticoid Receptor Antagonists; D008901:Mineralocorticoids; D017346:Protein Serine-Threonine Kinases; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D022021:Tacrolimus Binding Proteins; D013941:Thymine; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099159:Tacrolimus Binding Protein 5; C000606526:CORT118335