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Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation.
Gregory KJ, Conn PJ
(2015) Mol Pharmacol 88: 188-202
MeSH Terms: Allosteric Site, Benzhydryl Compounds, Central Nervous System, Drug Design, Humans, Molecular Targeted Therapy, Protein Conformation, Receptors, Metabotropic Glutamate
Show Abstract · Added February 18, 2016
The metabotropic glutamate (mGlu) receptors are a group of eight family C G protein-coupled receptors that are expressed throughout the central nervous system (CNS) and periphery. Within the CNS the different subtypes are found in neurons, both pre- and/or postsynaptically, where they mediate modulatory roles and in glial cells. The mGlu receptor family provides attractive targets for numerous psychiatric and neurologic disorders, with the majority of discovery programs focused on targeting allosteric sites, with allosteric ligands now available for all mGlu receptor subtypes. However, the development of allosteric ligands remains challenging. Biased modulation, probe dependence, and molecular switches all contribute to the complex molecular pharmacology exhibited by mGlu receptor allosteric ligands. In recent years we have made significant progress in our understanding of this molecular complexity coupled with an increased understanding of the structural basis of mGlu allosteric modulation.
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
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8 MeSH Terms
Survivorship: cognitive function, version 1.2014.
Denlinger CS, Ligibel JA, Are M, Baker KS, Demark-Wahnefried W, Friedman DL, Goldman M, Jones L, King A, Ku GH, Kvale E, Langbaum TS, Leonardi-Warren K, McCabe MS, Melisko M, Montoya JG, Mooney K, Morgan MA, Moslehi JJ, O'Connor T, Overholser L, Paskett ED, Raza M, Syrjala KL, Urba SG, Wakabayashi MT, Zee P, McMillian NR, Freedman-Cass DA, National Comprehensive Cancer Network
(2014) J Natl Compr Canc Netw 12: 976-86
MeSH Terms: Adaptation, Psychological, Benzhydryl Compounds, Brain Neoplasms, Central Nervous System Stimulants, Cognition Disorders, Fatigue, Humans, Methylphenidate, Modafinil, Occupational Therapy, Pain Management, Quality of Life, Sleep Wake Disorders, Survival Rate, Treatment Outcome, Wakefulness-Promoting Agents
Show Abstract · Added May 29, 2020
Cognitive impairment is a common complaint among cancer survivors and may be a consequence of the tumors themselves or direct effects of cancer-related treatment (eg, chemotherapy, endocrine therapy, radiation). For some survivors, symptoms persist over the long term and, when more severe, can impact quality of life and function. This section of the NCCN Guidelines for Survivorship provides assessment, evaluation, and management recommendations for cognitive dysfunction in survivors. Nonpharmacologic interventions (eg, instruction in coping strategies; management of distress, pain, sleep disturbances, and fatigue; occupational therapy) are recommended, with pharmacologic interventions as a last line of therapy in survivors for whom other interventions have been insufficient.
Copyright © 2014 by the National Comprehensive Cancer Network.
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MeSH Terms
The effect of adjunctive armodafinil on cognitive performance and psychopathology in antipsychotic-treated patients with schizophrenia/schizoaffective disorder: a randomized, double-blind, placebo-controlled trial.
Bobo WV, Woodward ND, Sim MY, Jayathilake K, Meltzer HY
(2011) Schizophr Res 130: 106-13
MeSH Terms: Adolescent, Adult, Antipsychotic Agents, Benzhydryl Compounds, Cognition Disorders, Double-Blind Method, Factor Analysis, Statistical, Female, Humans, Male, Middle Aged, Modafinil, Neuropsychological Tests, Psychiatric Status Rating Scales, Psychopathology, Psychotic Disorders, Retrospective Studies, Schizophrenia, Treatment Outcome, Young Adult
Show Abstract · Added February 15, 2016
BACKGROUND - The efficacy, safety and tolerability of adjunctive armodafinil for cognitive performance, and negative and affective symptoms, were examined in 60 patients with schizophrenia or schizoaffective disorder.
METHOD - This was a 6-week, double-blind, placebo-controlled, fixed dose trial of armodafinil (150 mg/d) augmentation in patients with clinically stable schizophrenia or schizoaffective disorder. Cognition, psychopathology, alertness/wakefulness and adverse effects were assessed with standardized rating instruments. The primary endpoint was performance on measures of attention/vigilance.
RESULTS - Patients were randomly allocated to adjunctive armodafinil or placebo. There was a significant Drug×Time interaction effect for attention/vigilance, due to modest non-significant worsening in the armodafinil group and improvement in the armodafinil group [CPT-Pairs d', F(1,40)=6.2, p=0.017]. However, it became non-significant after correction for multiple comparisons. There were no differences between armodafinil and placebo in other cognitive domains or psychopathology measures. However, armodafinil was associated with significant improvement in the Scale for the Assessment of Negative Symptoms (SANS) anhedonia-asociality [F(1,41)=4.1, p=0.05].
CONCLUSIONS - There were no significant differences in neurocognitive measures between adjunctive armodafinil and placebo in this 6-week study. Armodafinil improved anhedonia-asociality, but not other negative symptom domains.
Copyright © 2011 Elsevier B.V. All rights reserved.
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20 MeSH Terms
Occurrence of bisphenol A in indoor dust from two locations in the eastern United States and implications for human exposures.
Loganathan SN, Kannan K
(2011) Arch Environ Contam Toxicol 61: 68-73
MeSH Terms: Adult, Air Pollution, Indoor, Benzhydryl Compounds, Child, Dust, Environmental Monitoring, Housing, Humans, Kentucky, New York, Phenols
Show Abstract · Added January 5, 2016
Bisphenol A (BPA) is used in the production of polycarbonate plastics and epoxy resins, which are used in many consumer products. Sources of human exposures to BPA include packaged and canned food products, indoor air, and dust ingestion. Information on the relative contributions of the pathways to BPA exposures is limited. In this study, we measured concentrations BPA in indoor dust collected from two locations in the Eastern United States and evaluated the contribution of dust to total BPA exposures. BPA was found in 95% of the dust samples analyzed (n = 56) at concentrations ranging from <0.5 to 10,200 ng/g (mean 843; median 422). The median values for BPA intake by way of the ingestion of dust by adults and toddlers were calculated to be 0.35 and 5.63 ng/kg body weight/day. These estimated exposure doses of BPA through dust ingestion are of the same order of magnitude as the recently reported low concentrations that induced health effects in laboratory animal studies. The contribution of dust to total human BPA intake was estimated to be <1%, however, suggesting that dietary intake is the predominant source of exposures in humans.
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11 MeSH Terms
Renal function, bisphenol A, and alkylphenols: results from the National Health and Nutrition Examination Survey (NHANES 2003-2006).
You L, Zhu X, Shrubsole MJ, Fan H, Chen J, Dong J, Hao CM, Dai Q
(2011) Environ Health Perspect 119: 527-33
MeSH Terms: Adult, Aged, Benzhydryl Compounds, Biomarkers, Environmental Exposure, Environmental Pollutants, Female, Humans, Kidney, Male, Middle Aged, Nutrition Surveys, Phenols, Triclosan
Show Abstract · Added March 5, 2014
BACKGROUND - Urinary excretion of bisphenol A (BPA) and alkylphenols (APs) was used as a biomarker in most previous studies, but no study has investigated whether urinary excretion of these environmental phenols differed by renal function.
OBJECTIVE - We estimated the association between renal function and urinary excretion of BPA and APs.
METHODS - Analyses were conducted using data from the National Health and Nutrition Examination Survey (NHANES) 2003-2006. Renal function was measured as estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease (MDRD) Study equation and by the newly developed Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Regression models were used to calculate geometric means of urinary BPA and APs excretion by eGFR category (≥ 90, 60-90, < 60 mL/min/m(2)) after adjusting for potential confounding factors.
RESULTS - When we used the MDRD Study equation, participants without known renal disease (n=2,573), 58.2% (n=1,499) had mildly decreased renal function or undiagnosed chronic kidney disease. The adjusted geometric means for urinary BPA excretion decreased with decreasing levels of eGFR (p for trend=0.04). The associations appeared primarily in females (p for trend=0.03). Urinary triclosan excretion decreased with decreasing levels of eGFR (p for trend < 0.01) for both males and females, and the association primarily appeared in participants < 65 years of age. The association between BPA and eGFR was nonsignificant when we used the CKD-EPI equation.
CONCLUSIONS - Urinary excretion of triclosan, and possibly BPA, decreased with decreasing renal function. The associations might differ by age or sex. Further studies are necessary to replicate our results and understand the mechanism.
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14 MeSH Terms
NTP-CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A.
Chapin RE, Adams J, Boekelheide K, Gray LE, Hayward SW, Lees PS, McIntyre BS, Portier KM, Schnorr TM, Selevan SG, Vandenbergh JG, Woskie SR
(2008) Birth Defects Res B Dev Reprod Toxicol 83: 157-395
MeSH Terms: Abnormalities, Drug-Induced, Administration, Oral, Animals, Benzhydryl Compounds, Databases, Factual, Environmental Exposure, Estrogens, Non-Steroidal, Female, Humans, Male, Maternal Exposure, Phenols, Pregnancy, Prenatal Exposure Delayed Effects, Reproduction, Risk
Added May 27, 2014
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16 MeSH Terms
The orexins/hypocretins and schizophrenia.
Deutch AY, Bubser M
(2007) Schizophr Bull 33: 1277-83
MeSH Terms: Benzhydryl Compounds, Brain, Central Nervous System Stimulants, Chromosomes, Human, Pair 17, Humans, Intracellular Signaling Peptides and Proteins, Modafinil, Neuropeptides, Orexins, Schizophrenia
Show Abstract · Added May 27, 2014
Advances in molecular biology have led to new peptides and proteins being discovered on a regular basis, including the isolation of a number of neurotransmitter candidates. Rarely, however, do these immediately capture the attention of the scientific community. The isolation and characterization of the orexin/hypocretin peptides a decade ago resulted in a slew of studies that have helped clarified their diverse functions, including prominent roles in arousal and appetitive behavior. A number of recent studies have detailed the role of the orexins/hypocretins in attention and cognition and uncovered an involvement in schizophrenia and the mechanisms of action of antipsychotic drugs (APDs). This issue of Schizophrenia Bulletin presents several articles that review our current understanding and point to future directions for the study of the orexins/hypocretins in schizophrenia and APD actions.
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10 MeSH Terms
Degradation pathway of bisphenol A: does ipso substitution apply to phenols containing a quaternary alpha-carbon structure in the para position?
Kolvenbach B, Schlaich N, Raoui Z, Prell J, Zühlke S, Schäffer A, Guengerich FP, Corvini PF
(2007) Appl Environ Microbiol 73: 4776-84
MeSH Terms: Benzhydryl Compounds, Biodegradation, Environmental, Carbon Radioisotopes, Chromatography, High Pressure Liquid, Models, Chemical, Molecular Structure, Oxygen Isotopes, Phenols, Sphingomonas, Stereoisomerism
Show Abstract · Added March 26, 2014
The degradation of bisphenol A and nonylphenol involves the unusual rearrangement of stable carbon-carbon bonds. Some nonylphenol isomers and bisphenol A possess a quaternary alpha-carbon atom as a common structural feature. The degradation of nonylphenol in Sphingomonas sp. strain TTNP3 occurs via a type II ipso substitution with the presence of a quaternary alpha-carbon as a prerequisite. We report here a new degradation pathway of bisphenol A. Consequent to the hydroxylation at position C-4, according to a type II ipso substitution mechanism, the C-C bond between the phenolic moiety and the isopropyl group of bisphenol A is broken. Besides the formation of hydroquinone and 4-(2-hydroxypropan-2-yl)phenol as the main metabolites, further compounds resulting from molecular rearrangements consistent with a carbocationic intermediate were identified. Assays with resting cells or cell extracts of Sphingomonas sp. strain TTNP3 under an (18)O(2) atmosphere were performed. One atom of (18)O(2) was present in hydroquinone, resulting from the monooxygenation of bisphenol A and nonylphenol. The monooxygenase activity was dependent on both NADPH and flavin adenine dinucleotide. Various cytochrome P450 inhibitors had identical inhibition effects on the conversion of both xenobiotics. Using a mutant of Sphingomonas sp. strain TTNP3, which is defective for growth on nonylphenol, we demonstrated that the reaction is catalyzed by the same enzymatic system. In conclusion, the degradation of bisphenol A and nonylphenol is initiated by the same monooxygenase, which may also lead to ipso substitution in other xenobiotics containing phenol with a quaternary alpha-carbon.
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10 MeSH Terms
A randomized, double-blind, crossover trial of modafinil on mood.
Taneja I, Haman K, Shelton RC, Robertson D
(2007) J Clin Psychopharmacol 27: 76-9
MeSH Terms: Administration, Oral, Adult, Affect, Benzhydryl Compounds, Central Nervous System Stimulants, Cross-Over Studies, Double-Blind Method, Female, Hospitalization, Humans, Male, Modafinil, Reference Values
Show Abstract · Added December 10, 2013
Modafinil, a medication for the excessive sleepiness associated with narcolepsy, has been hypothesized to improve not just alertness but mood as well. The purpose of this study was to determine how treatment with modafinil affects mood in healthy volunteers. Normal healthy volunteers (n = 12, 10 men and 2 women; 30-44 years) underwent a 3-day, counterbalanced, randomized, crossover, inpatient trial of modafinil (400 mg daily) versus placebo with 4-day washout period between 2 treatments. Mood was assessed daily using both the Positive and Negative Affect Schedule and a general mood scale, which consisted of 10 bipolar adjective ratings based on a severity scale ranging from 1 to 10. Modafinil increased general mood and Negative Affect scales relative to placebo and had a significant effect on Positive Affect scales. These results suggest that modafinil may have general mood-elevating effects accompanied by increased negative affect (anxiety). The findings may have implications for clinical practice, in particular for the adjunctive use of modafinil in treatment-resistant depression.
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13 MeSH Terms
Modafinil elicits sympathomedullary activation.
Taneja I, Diedrich A, Black BK, Byrne DW, Paranjape SY, Robertson D
(2005) Hypertension 45: 612-8
MeSH Terms: Adrenal Medulla, Adult, Benzhydryl Compounds, Cardiovascular System, Catecholamines, Central Nervous System Stimulants, Cross-Over Studies, Diuresis, Double-Blind Method, Electrolytes, Female, Humans, Male, Middle Aged, Modafinil, Muscle, Skeletal, Reference Values, Sympathetic Nervous System
Show Abstract · Added December 10, 2013
The autonomic effects of modafinil (Provigil), a psychostimulant widely used to attenuate fatigue and promote wakefulness, are currently unexplored. We assessed the effect of modafinil on autonomic nervous system. We compared oral modafinil (400 mgx1) versus placebo in 12 healthy hospitalized normal subjects in a randomized double-blind, placebo-controlled cross-over study for 3 days each with subjects in 150 mEq sodium, 70 mEq potassium balance at the Vanderbilt General Clinical Research Center. Modafinil increased resting heart rate (9.2+/-2.0 bpm; mean [+/-SE]; 95% confidence interval [CI], 4.7 to 13.6; P=0.001), resting systolic blood pressure (7.3+/-3.2 mm Hg; 95% CI, 0.2 to 14.4; P=0.044), and resting diastolic blood pressure (5.3+/-1.7 mm Hg; 95% CI, 1.4 to 9.1 mm Hg; P<0.012). Modafinil elicited a 42% higher orthostatic increase in plasma norepinephrine (0.8+/-0.3 nmol/L; 95% CI, 0.2 to 1.3; P=0.01), and caused a 33% increase in urine norepinephrine (5.1+/-1.1 nmol/L creatinine per day; 95% CI, 2.7 to 7.4, P=0.001), and an 81% increase in urine epinephrine (1.3+/-0.2 nmol/L creatinine per day; 95% CI, 1 to 2; P<0.001). The peroneal microneurographic sympathetic activity was attenuated by modafinil during orthostatic tilt (P<0.001). alpha1-Adrenoreceptor function was maintained. Modafinil substantially perturbs autonomic cardiovascular regulation by increase in heart rate and blood pressure. Autonomic changes of this magnitude encourage caution in use of modafinil in patients with cardiovascular disease.
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18 MeSH Terms