ChemInform Abstract: Synthesis of Novel Imidazobenzodiazepines Selective for the α5. beta.2γ2 (Bz5) GABAA/Benzodiazepine Receptor Subtype.

ChemInform ◽  
2010 ◽  
Vol 27 (21) ◽  
pp. no-no
Author(s):  
R. LIU ◽  
P. ZHANG ◽  
R. M. MCKERNAN ◽  
K. WAFFORD ◽  
J. M. COOK
Keyword(s):  
Benzodiazepine Receptor ◽  
Receptor Subtype

scholarly journals Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [11C]Ro15-4513 PET Images

2012 ◽  
Vol 32 (4) ◽  
pp. 731-744 ◽  
Author(s):  
James FM Myers ◽  
Lula Rosso ◽  
Ben J Watson ◽  
Sue J Wilson ◽  
Nicola J Kalk ◽  
...  
Keyword(s):  
Spectral Analysis ◽  
A Priori ◽  
Benzodiazepine Receptor ◽  
Brain Regions ◽  
Complex Model ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Time Activity ◽  
Positron Emission ◽  
The Impact

This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume ( VT) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that Zolpidem caused a significant VT decrease (~10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean ± s.d.: 71% ± 41%), presumed to reflect α1-subtype binding, but not another (13% ± 22%), presumed to reflect α5. The proposed method for [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.

Clinical Management of Insomnia

2017 ◽  
Author(s):  
Timothy Roehrs ◽  
Thomas Roth
Keyword(s):  
Relaxation Training ◽  
Behavioral Therapy ◽  
Receptor Site ◽  
Benzodiazepine Receptor ◽  
Female Gender ◽  
Consensus Conference ◽  
Receptor Subtype ◽  
Behavioral Treatments ◽  
Hypnotic Efficacy ◽  
Electroencephalographic Activity

Insomnia is the most common sleep disorder, with a prevalence of around 20%. The clearest risk factors are female gender and the presence of a psychiatric or medical disorder. The most important conceptual change in our understanding of insomnia, defined in the National Institutes of Health 2005 consensus conference, is that insomnia is a disorder itself rather than a symptom of another disorder. Specifically, insomnia is a disorder of hyperarousal. Insomniacs do not have an abnormal sleep homeostat or circadian system but rather an overactivated wake system. Cognitively, patients often complain they cannot “shut [their] brain down.” Physiologic correlates include elevated brain metabolism, increased fast electroencephalographic activity, and increased autonomic, metabolic, and hypothalamic-pituitary-adrenal axis activity. Treatment for insomnia can be divided into two categories, behavioral and pharmacologic. Another important categorization relates to self-treatment (sleep hygiene and over-the-counter drugs) versus clinician-directed therapy (cognitive-behavioral therapy for insomnia [CBT-I] and prescribed hypnotics). Among behavioral treatments are sleep restriction, stimulus control, relaxation training, and cognitive therapy. The most widely used behavioral therapy is a combination of the four treatment components referred to collectively as CBT-I. The majority of Food and Drug Administration (FDA)-approved hypnotics are drugs that occupy the benzodiazepine receptor site, which is part of the GABAA receptor complex. The hypnotic efficacy of the FDA-approved benzodiazepine receptor agonists (BzRAs) has been well documented using objective polysomnography and subjective measures of sleep induction and duration. Many BzRA side effects are associated with the desired sedative effects of the drug and relate to the pharmacokinetics, receptor subtype affinities, and dose of the drug. Key words: behavioral therapy, GABA, histamine, insomnia disorder, melatonin, orexin, pathophysiology, pharmacotherapy

scholarly journals Imaging the GABA-Benzodiazepine Receptor Subtype Containing the α5-Subunit In Vivo with [11C]Ro15 4513 Positron Emission Tomography

2002 ◽  
Vol 22 (7) ◽  
pp. 878-889 ◽  
Author(s):  
Anne Lingford-Hughes ◽  
Susan P. Hume ◽  
Adrian Feeney ◽  
Ella Hirani ◽  
Safiye Osman ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Benzodiazepine Receptors ◽  
Benzodiazepine Receptor ◽  
Occipital Cortex ◽  
Input Function ◽  
Emission Tomography ◽  
Receptor Subtype ◽  
Receptor Localization ◽  
Positron Emission

There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The α5-containing subtype is highly expressed in the hippocampus, and selective α5 inverse agonists (which decrease tonic GABA inhibition) are being developed as potential memory-enhancing agents. Evidence for such receptor localization and specialization in humans in vivo is lacking because the widely used probes for imaging the GABA-benzodiazepine receptors, [11C]flumazenil and [123I]iomazenil, appear to reflect binding to the α1 subtype, based on its distribution and affinity of flumazenil for this subtype. The authors characterized for positron emission tomography (PET) a radioligand from Ro15 4513, the binding of which has a marked limbic distribution in the rat and human brain in vivo. Competition studies in vivo in the rat revealed that radiolabeled Ro15 4513 uptake was reduced to nonspecific levels only by drugs that have affinity for the α5 subtype (flunitrazepam, RY80, Ro15 4513, L655,708), but not by the α1 selective agonist, zolpidem. Quantification of [11C]Ro15 4513 PET was performed in humans using a metabolite-corrected plasma input function. [11C]Ro15 4513 uptake was relatively greater in limbic areas compared with [11C]flumazenil, but lower in the occipital cortex and cerebellum. The authors conclude that [11C]Ro15 4513 PET labels in vivo the GABA-benzodiazepine receptor containing the α5 subtype in limbic structures and can be used to further explore the functional role of this subtype in humans.

Nuclear receptors in disease: the oestrogen receptors

2004 ◽  
Vol 40 ◽  
pp. 157-167 ◽  
Author(s):  
Maria Nilsson ◽  
Karin Dahlman-Wright ◽  
Jan-Åke Gustafsson
Keyword(s):  
Nuclear Receptors ◽  
Target Genes ◽  
Receptor Subtype ◽  
Target Tissue ◽  
Oestrogen Receptors ◽  
Nucleotide Polymorphisms ◽  
Cell Type ◽  
Single Nucleotide ◽  
Beneficial Effects ◽  
The Family

For several decades, it has been known that oestrogens are essential for human health. The discovery that there are two oestrogen receptors (ERs), ERalpha and ERbeta, has facilitated our understanding of how the hormone exerts its physiological effects. The ERs belong to the family of ligand-activated nuclear receptors, which act by modulating the expression of target genes. Studies of ER-knockout (ERKO) mice have been instrumental in defining the relevance of a given receptor subtype in a certain tissue. Phenotypes displayed by ERKO mice suggest diseases in which dysfunctional ERs might be involved in aetiology and pathology. Association between single-nucleotide polymorphisms (SNPs) in ER genes and disease have been demonstrated in several cases. Selective ER modulators (SERMs), which are selective with regard to their effects in a certain cell type, already exist. Since oestrogen has effects in many tissues, the goal with a SERM is to provide beneficial effects in one target tissue while avoiding side effects in others. Refined SERMs will, in the future, provide improved therapeutic strategies for existing and novel indications.

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