In Vivo Characterization and Dynamic Receptor Occupancy Imaging of TPA023B, an α2/α3/α5 Subtype Selective γ-Aminobutyric Acid–A Partial Agonist

2008 ◽  
Vol 64 (2) ◽  
pp. 153-161 ◽  
Author(s):  
Koen Van Laere ◽  
Guy Bormans ◽  
Sandra M. Sanabria-Bohórquez ◽  
Tjibbe de Groot ◽  
Patrick Dupont ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Receptor Occupancy ◽  
Aminobutyric Acid ◽  
In Vivo Characterization ◽  
Subtype Selective

Differentiating the role of γ-aminobutyric acid type A (GABAA) receptor subtypes

2004 ◽  
Vol 32 (3) ◽  
pp. 553-556 ◽  
Author(s):  
K.A. Wafford ◽  
A.J. Macaulay ◽  
R. Fradley ◽  
G.F. O'Meara ◽  
D.S. Reynolds ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Acid Type ◽  
Gabaa Receptor Subtypes ◽  
Subtype Selective

The inhibitory tone maintained throughout the central nervous system relies predominantly on the activity of neuronal GABAA (γ-aminobutyric acid type A) receptors. This receptor family comprises various subtypes that have unique regional distributions, but little is known about the role played by each subtype. The majority of the receptors contain a γ2 subunit and are sensitive to modulation by BZs (benzodiazepines), but differ with regard to α and β subunits. Mutagenesis studies combined with molecular modelling have enabled a greater understanding of receptor structure and dynamics. This can now be extended to in vivo activity through translation to genetically modified mice containing these mutations. Ideally, the mutation should leave normal receptor function intact, and this is the case with mutations affecting the BZ-binding site of the GABAA receptor. We have generated mutations, which affect the BZ site of different α subunits, to enable discrimination of the various behavioural consequences of BZ drug action. This has aided our understanding of the roles played by individual GABAA receptor subtypes in particular behaviours. We have also used this technique to explore the role of different β subunits in conferring the anaesthetic activity of etomidate. This technique together with the development of subtype-selective compounds facilitates our understanding of the roles played by each receptor subtype.

scholarly journals Cerebral serotonin release correlates with [11C]AZ10419369 PET measures of 5-HT1B receptor binding in the pig brain

2017 ◽  
Vol 38 (7) ◽  
pp. 1243-1252 ◽  
Author(s):  
Louise M Jørgensen ◽  
Pia Weikop ◽  
Claus Svarer ◽  
Ling Feng ◽  
Sune H Keller ◽  
...  
Keyword(s):  
Spatial Information ◽  
Partial Agonist ◽  
Receptor Occupancy ◽  
Serotonin Release ◽  
Serotonin Level ◽  
Imaging Data ◽  
Pig Brain ◽  
Positron Emission ◽  
Acute Changes

Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively capture temporal and spatial information about acute changes in brain neurotransmitter systems. We here evaluate the 5-HT1B receptor partial agonist PET radioligand, [11C]AZ10419369, for its sensitivity to detect changes in endogenous cerebral serotonin levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain serotonin levels, we compared the [11C]AZ10419369 PET signal in the pig brain to simultaneous measurements of extracellular serotonin levels with microdialysis after various acute interventions (saline, escitalopram, fenfluramine). The interventions increased the cerebral extracellular serotonin levels to two to six times baseline, with fenfluramine being the most potent pharmacological enhancer of serotonin release. The interventions induced a varying degree of decline in [11C]AZ10419369 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular serotonin level in the pig brain and the 5-HT1B receptor occupancy indicates that [11C]AZ10419369 binding is sensitive to changes in endogenous serotonin levels to a degree equivalent to that reported of [11C]raclopride to dopamine, a much used approach to detect in vivo change in cerebral dopamine.

EEG-β/γ spectral power elevation in rat: a translatable biomarker elicited by GABAAα2/3-positive allosteric modulators at nonsedating anxiolytic doses

2015 ◽  
Vol 113 (1) ◽  
pp. 116-131 ◽  
Author(s):  
Edward P. Christian ◽  
Dean H. Snyder ◽  
Wei Song ◽  
David A. Gurley ◽  
Joanne Smolka ◽  
...  
Keyword(s):  
Spectral Power ◽  
Dose Range ◽  
Receptor Occupancy ◽  
Brain Regions ◽  
Intrinsic Activity ◽  
Conflict Model ◽  
Subtype Selective ◽  
Dose Dependent

Benzodiazepine drugs, through interaction with GABAAα1, GABAAα2,3, and GABAAα5 subunits, modulate cortical network oscillations, as reflected by a complex signature in the EEG power spectrum. Recent drug discovery efforts have developed GABAAα2,3-subunit-selective partial modulators in an effort to dissociate the side effect liabilities from the efficacy imparted by benzodiazepines. Here, we evaluated rat EEG and behavioral end points during dosing of nine chemically distinct compounds that we confirmed statistically to selectively to enhance GABAAα2,3-mediated vs. GABAAα1 or GABAAα5 currents in voltage clamped oocytes transfected with those GABAA subunits. These compounds were shown with in vivo receptor occupancy techniques to competitively displace [3H]flumazenil in multiple brain regions following peripheral administration at increasing doses. Over the same dose range, the compounds all produced dose-dependent EEG spectral power increases in the β- and and γ-bands. Finally, the dose range that increased γ-power coincided with that eliciting punished over unpunished responding in a behavioral conflict model of anxiety, indicative of anxiolysis without sedation. EEG γ-band power increases showed a significant positive correlation to in vitro GABAAα2,3 modulatory intrinsic activity across the compound set, further supporting a hypothesis that this EEG signature was linked specifically to pharmacological modulation of GABAAα2,3 signaling. These findings encourage further evaluation of this EEG signature as a noninvasive clinical translational biomarker that could ultimately facilitate development of GABAAα2,3-subtype-selective drugs for anxiety and potentially other indications.

In Vivo Characterization of Muscarinic Receptor Subtypes That Mediate Vasodilatation in Patients With Essential Hypertension

Hypertension ◽  
1995 ◽  
Vol 26 (1) ◽  
pp. 70-77 ◽  
Author(s):  
Tobias A. Bruning ◽  
Peter C. Chang ◽  
Maarten G.C. Hendriks ◽  
Pieter Vermeij ◽  
Martin Pfaffendorf ◽  
...  
Keyword(s):  
Essential Hypertension ◽  
Muscarinic Receptor ◽  
Receptor Subtypes ◽  
Muscarinic Receptor Subtypes ◽  
In Vivo Characterization
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