ABSTRACT
BACKGROUND: Bisphenol A (BPA) and other related chemical compounds may be components used in the manufacturing process of resin-based composite dental restorative material. The purpose of the authors' study was to assess salivary and urinary concentrations of BPA and other compounds before and after placement of resin-based composite dental restorations. METHODS: The authors collected saliva and urine from 172 participants receiving composite restorations before and as long as 30 hours after placement of composite restorations. The authors analyzed saliva specimens from 151 participants and urine specimens from 171 participants for concentrations of BPA and five related compounds by using liquid chromatography/mass spectrometry (LC/MS). RESULTS: Salivary concentrations of BPA and some related compounds increased immediately (within one hour) after composite placement. Salivary concentrations of BPA and most study compounds returned to prerestoration levels within eight hours after composite placement. With the exception of a 43 percent increase in BPA, concentrations of the study compounds in urine returned to prerestoration levels nine to 30 hours after restoration placement. Concentrations in saliva were lower when a rubber dam was used; however, rubber dam use appeared to have no effect on urinary concentrations of the measured compounds during the study period. The authors observed similar changes in study compound levels in both saliva and urine between participants who received anterior restorations and those who received posterior restorations. CONCLUSIONS: Placement of resin-based composite restorations was associated with detectable increases in saliva of BPA and other study compounds within one hour after restoration placement and an increased concentration of BPA in urine nine to 30 hours after restoration placement. Rubber dam use did not reduce the absorption of BPA (measured as BPA level in urine) during the study. CLINICAL IMPLICATIONS: Additional studies are needed to address how long BPA levels in urine associated with composite placement remain elevated to aid in better understanding of the clearance rates of BPA and other study compounds.
Subject(s)
Benzhydryl Compounds/analysis , Composite Resins/analysis , Dental Materials/analysis , Dental Restoration, Permanent , Phenols/analysis , Saliva/chemistry , Acrylic Resins/chemistry , Adult , Benzhydryl Compounds/chemistry , Benzhydryl Compounds/urine , Chromatography, Liquid , Composite Resins/chemistry , Dental Materials/chemistry , Epoxy Compounds/analysis , Female , Follow-Up Studies , Humans , Male , Mass Spectrometry , Methacrylates/analysis , Phenols/chemistry , Phenols/urine , Polyethylene Glycols/analysis , Polymethacrylic Acids/analysis , Polyurethanes/chemistry , Rubber DamsABSTRACT
OBJECTIVE: To test the role of ERbeta in the control of estrogen-dependent thermoregulation in rats. METHODS: Test the ability of an ERbeta-selective ligand to suppress the elevation in basal rat tail skin temperature (TST) caused by ovariectomy (OVX). RESULTS: ERbeta-19 is a tetrahydrofluorenone ERbeta-selective ligand that displaces 0.1 nM estradiol from ERbeta with an IC50 of 1.8 nM compared to an IC50 of 141 nM for ERalpha. Like estradiol, it acts as an agonist on ERbeta-mediated transactivation and transrepression with 25- and 60-fold selectivity, respectively, over ERalpha-controlled transcription. Administration of estradiol to estrogen-depleted rats suppresses the ovariectomy-induced elevation of TST. Similar treatment of OVX rats with ERbeta-19 also results in suppression of elevated TST. However, in contrast to estradiol, ERbeta-19 does not suppress body weight, does not increase uterine weight, nor does it stimulate uterocalin biomarker expression which is under the control of ERalpha. Thus, the ERbeta-19 suppression of rat TST is mediated by ERbeta without eliciting the activity of ERalpha. CONCLUSION: Estrogen-sensitive thermoregulation in ovariectomized rats can be controlled by an ERbeta-selective ligand.
Subject(s)
Body Temperature Regulation/genetics , Estradiol/pharmacology , Estrogen Receptor beta/agonists , Fluorenes/pharmacology , Skin Temperature/genetics , Animals , Body Temperature Regulation/physiology , Body Weight/drug effects , Estradiol/genetics , Estradiol/metabolism , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Female , Gene Expression Regulation , Ligands , Lipocalins/metabolism , Organ Size/drug effects , Ovariectomy , Rats , Rats, Sprague-Dawley , Skin Temperature/physiology , Tail , Uterus/metabolismABSTRACT
A novel class of indole ligands for estrogen receptor alpha have been discovered which exhibit potent affinity and high selectivity. Substitution of the bazedoxifene skeleton to the linker present in the HTS lead 1a provided 22b which was found to be 130-fold alpha-selective and acted as an antagonist of estradiol activity in uterine tissue and MCF-7 cancer cells.
Subject(s)
Estrogen Receptor alpha/antagonists & inhibitors , Indoles/chemistry , Indoles/pharmacokinetics , Breast Neoplasms/drug therapy , Cell Line, Tumor , Estrogen Antagonists/chemistry , Estrogen Antagonists/pharmacology , Female , Humans , Inhibitory Concentration 50 , Ligands , Uterus/drug effectsABSTRACT
Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst(1)-sst(5)) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst(2), whereas B cells express sst(5). In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst(2)-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst(2)-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst(2)-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst(2) selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst(2)-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.
Subject(s)
Hypoglycemic Agents/pharmacology , Receptors, Somatostatin/agonists , Animals , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Dogs , Glucagon/metabolism , Growth Hormone/metabolism , In Vitro Techniques , Insulin/metabolism , Insulin/pharmacology , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Rats , Receptors, Somatostatin/geneticsABSTRACT
The enzyme 11beta-hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We report that pharmacologic inhibition of 11beta-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11beta-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11beta-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11beta-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Adamantane/analogs & derivatives , Arteriosclerosis/drug therapy , Azepines/administration & dosage , Enzyme Activation/drug effects , Enzyme Inhibitors/administration & dosage , Insulin Resistance , Triazoles/administration & dosage , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adamantane/administration & dosage , Animals , Aorta/metabolism , Arteriosclerosis/complications , Arteriosclerosis/enzymology , Blood Glucose/drug effects , Cortisone/metabolism , Diet, Atherogenic , Disease Models, Animal , Fatty Acids/blood , Hydrocortisone , Insulin/blood , Male , Mice , Mice, Inbred ICR , Mice, Knockout , Syndrome , Triglycerides/bloodABSTRACT
Adamantyl triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They are active both in in vitro and in in vivo pharmacodynamic models. The synthesis and structure-activity relationships of these inhibitors are presented.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Triazoles/chemical synthesis , Adamantane/chemical synthesis , Adamantane/pharmacokinetics , Adamantane/pharmacology , Animals , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Metabolic Syndrome/drug therapy , Mice , Pharmacokinetics , Structure-Activity Relationship , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
An optimized side chain for dihydrobenzoxathiin SERAMs was discovered and attached to four dihydrobenzoxathiin platforms. The novel SERAMs show exceptional estrogen antagonist activity in uterine tissue and an MCF-7 breast cancer cell assay.
Subject(s)
Oxathiins/chemical synthesis , Receptors, Estrogen/chemistry , Selective Estrogen Receptor Modulators/chemical synthesis , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Dose-Response Relationship, Drug , Estrogen Antagonists/chemical synthesis , Estrogen Antagonists/pharmacology , Female , Humans , Oxathiins/pharmacology , Rats , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Uterus/drug effects , Uterus/growth & developmentABSTRACT
BACKGROUND: Distinct expression patterns of estrogen receptor (ER)-alpha and ER-beta are displayed in the murine central nervous system. ER-beta is the predominant form of the receptor expressed in the murine midbrain dorsal raphe nucleus (DRN). Tryptophan hydroxylase (TPH) is abundantly expressed in the serotonergic neurons of the DRN and is regulated by estrogen in both the monkey and the guinea pig. METHODS: In this study we used immunocytochemistry to show that ER-beta and TPH are colocalized in the serotonergic cells of the murine DRN. We utilized the ER-alpha and ER-beta gene deletion mouse models and in situ hybridization to demonstrate that ER-beta is responsible for regulating TPH1 mRNA expression. RESULTS: Estrogen increased TPH1 mRNA expression in the DRN of wild type and ER-alpha knockout mice (alpha-ERKO) but not ER-beta knockouts (beta-ERKO). CONCLUSIONS: These data indicate that ER-beta is responsible for mediating estrogen regulated TPH1 expression in the murine DRN.
Subject(s)
Estrogen Receptor beta/physiology , Mesencephalon/metabolism , Raphe Nuclei/metabolism , Tryptophan Hydroxylase/biosynthesis , Animals , Cells, Cultured , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/physiology , Estrogen Receptor beta/genetics , Immunohistochemistry , In Situ Hybridization , Mesencephalon/enzymology , Mice , Mice, Inbred C57BL , Neurons/metabolism , Ovariectomy , Raphe Nuclei/enzymology , Serotonin/physiologyABSTRACT
The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).
Subject(s)
Chromans/chemistry , Chromans/pharmacology , Estrogen Receptor alpha/metabolism , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Animals , Binding Sites , Cell Line , Female , Gene Expression/drug effects , Humans , Ligands , Models, Chemical , Molecular Structure , Organ Size , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Uterus/drug effectsABSTRACT
The ring oxygen and sulfur analogs of lasofoxifene, 1a and 1b, were synthesized in an attempt to impart ERalpha selectivity, as found in the closely related dihydrobenzoxathiin compound I, recently discovered in these laboratories. The resulting isochroman and isothiochroman compounds were found to exhibit equipotent binding affinities to the ER isoforms and were less active in the inhibition of estradiol-triggered uterine growth when compared to I and lasofoxifene.
Subject(s)
Chromans/chemical synthesis , Chromans/pharmacology , Estrogen Receptor alpha/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Estradiol/pharmacology , Female , Humans , Inhibitory Concentration 50 , Ligands , Models, Molecular , Protein Binding , Protein Isoforms , Structure-Activity Relationship , Uterus/drug effects , Uterus/growth & developmentABSTRACT
RATIONALE: The decrease in levels of estrogens (ER) that occurs in menopause has been correlated with depressive disorders, probably due to ER direct and/or indirect effects in the brain, where these hormones act through both genomic (i.e. interaction as transcription factors with nuclear receptors ER-alpha and ER-beta) and non-genomic (i.e. binding with cell-membrane receptors) mechanisms. With respect to mood related disorders the interaction between ER-beta and the serotonin (5-HT) system is highly relevant. 17beta-Estradiol (E2) induces expression of the enzyme implicated in 5-HT synthesis - tryptophan hydroxylase (TPH), and this effect is mediated through ER-beta located in 5-HT cell bodies of the dorsal raphe nucleus (DRN). OBJECTIVE: The present studies tested the hypothesis that E2 induces antidepressant-like effects in female ovariectomized (OVX) mice, and that expression of ER-beta is mandatory for such effects. METHODS: The Forced Swim Test (FST) was used in three experiments to assess (a) dose response effect of E2 in outbred and inbred mouse strains, (b) length of treatment necessary for effect, (c) and role of ER-beta receptors. RESULTS: E2 (100 or 200 microg/kg), as well as the antidepressant desipramine (DMI), significantly reduced total duration of immobility in the FST in mice from different strains. Four consecutive daily doses (200 microg/kg) were required for such effect, which was absent in mice lacking the gene coding for ER-beta (BERKO mice). CONCLUSION: These data suggest that E2-induced antidepressant-like effects in mice are mediated through activation of ER-beta. They offer preliminary support to the hypothesis that specific compounds acting at ER-beta may influence mood in postmenopausal women.
Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder/drug therapy , Estradiol/therapeutic use , Estrogen Receptor beta/deficiency , Estrogen Receptor beta/genetics , Swimming , Animals , Antidepressive Agents/pharmacology , Depressive Disorder/genetics , Depressive Disorder/metabolism , Estradiol/pharmacology , Female , Mice , Mice, Inbred C57BL , Mice, Knockout , Ovariectomy , Swimming/psychologyABSTRACT
A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
Subject(s)
Oxathiins/pharmacology , Pyrrolidines/chemistry , Receptors, Estrogen/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Ligands , Models, Molecular , Oxathiins/chemistry , Receptors, Estrogen/metabolismABSTRACT
A series of benzoxathiin SERAMs with bicyclic amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Ligands , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/metabolism , Animals , Bridged Bicyclo Compounds/pharmacology , Female , Kinetics , Models, Molecular , Molecular Conformation , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Uterus/drug effectsABSTRACT
A series of benzoxathiin SERAMs with heteroatom-substituted amine side chains was prepared. Minor modifications in the side chain resulted in significant effects on biological activity, especially in uterine tissue.
Subject(s)
Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/metabolism , Animals , Female , Kinetics , Ligands , Models, Molecular , Molecular Conformation , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Uterus/drug effectsABSTRACT
Dihydrobenzodithiin compounds (1-6) were prepared to explore the expansion of the dihydrobenzoxathiin lead compounds I-III as SERAMs (Selective Estrogen Receptor Alpha Modulators). The dihydrobenzodithiin compounds generally maintained a high degree of selectivity for ERalpha over ERbeta, however, they lacked the in vivo antagonism/agonism activity exhibited by the lead class in an immature rat uterine growth model.
Subject(s)
Heterocyclic Compounds, 2-Ring/chemical synthesis , Piperidines/chemical synthesis , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/chemical synthesis , Animals , Binding Sites , Cells, Cultured , Estrogen Receptor alpha , Estrogen Receptor beta , Female , Heterocyclic Compounds, 2-Ring/pharmacology , Inhibitory Concentration 50 , Ligands , Models, Biological , Piperidines/pharmacology , Rats , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Uterus/drug effects , Uterus/metabolismABSTRACT
Dihydrobenzoxathiin analogs (1-11) with modifications on the basic side chain region were prepared and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. The compounds generally maintained a high degree of selectivity for ERalpha over ERbeta, similar to the original lead compound I. Many of the compounds also maintained high potency in the inhibition of human carcinoma MCF-7 cell growth. However, all were less potent in the inhibition of estradiol-triggered uterine growth. This work demonstrates the sensitive nature of modification to the antagonist basic side chain region.
Subject(s)
Estrogen Antagonists/chemical synthesis , Oxathiins/chemical synthesis , Receptors, Estrogen/metabolism , Binding Sites , Cell Line, Tumor , Estrogen Antagonists/pharmacology , Estrogen Receptor alpha/antagonists & inhibitors , Estrogen Receptor beta/antagonists & inhibitors , Humans , Ligands , Oxathiins/pharmacology , Structure-Activity RelationshipABSTRACT
A series of estrogen receptor ligands based on a dihydrobenzoxathiin scaffold is described and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. The most active analogue, 22, was found to be 40-fold ERalpha selective in a competitive binding assay, and 22 demonstrated very potent in vivo antagonism of estradiol driven proliferation in an immature rat uterine weight gain assay.
Subject(s)
Estrogen Receptor alpha/chemistry , Oxathiins/pharmacology , Selective Estrogen Receptor Modulators/chemical synthesis , Animals , Binding, Competitive , Cell Line, Tumor , Cell Proliferation/drug effects , Estrogen Receptor beta/chemistry , Female , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Ligands , Organ Size , Oxathiins/chemical synthesis , Oxathiins/pharmacokinetics , Protein Binding , Rats , Rats, Sprague-Dawley , Selective Estrogen Receptor Modulators/pharmacokinetics , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship , Uterus/drug effectsABSTRACT
The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.
Subject(s)
Oxathiins/chemical synthesis , Selective Estrogen Receptor Modulators/chemical synthesis , Animals , Binding Sites , Binding, Competitive , Cell Line , Crystallography, X-Ray , Estrogen Receptor alpha , Estrogen Receptor beta , Female , Humans , Ligands , Models, Molecular , Molecular Conformation , Organ Size/drug effects , Oxathiins/chemistry , Oxathiins/pharmacology , Receptors, Estrogen/drug effects , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Stereoisomerism , Structure-Activity Relationship , Transcriptional Activation , Uterus/drug effectsABSTRACT
A series of 3-alkyl, 3-cycloalkyl, and 3-heteroaryl dihydrobenzoxathiin analogs 1 were prepared and evaluated for estrogen/anti-estrogen activity in both in vitro and in vivo models. In general, the compounds were found to exhibit a high degree of selectivity for ER alpha over ER beta, but were less potent than the original lead compound 1a in the inhibition of estradiol-driven uterine proliferation.
Subject(s)
Receptors, Estrogen/antagonists & inhibitors , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Animals , Cell Line , Cell Proliferation/drug effects , Female , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Inhibitory Concentration 50 , Ligands , Organ Size/drug effects , Rats , Structure-Activity Relationship , Uterus/cytologyABSTRACT
A class of flavanoids exhibiting a high degree of selectivity for ERalpha over ERbeta has been discovered. The most active analogue 6 was found to be 66-fold ERalpha-selective and demonstrated uterine estradiol antagonism.
