An Inverse Agonist Selective for α5 Subunit-Containing GABAA Receptors Enhances Cognition

@article{Dawson2006AnIA,
  title={An Inverse Agonist Selective for $\alpha$5 Subunit-Containing GABAA Receptors Enhances Cognition},
  author={G. R. Dawson and Karen A. Maubach and Neil Collinson and Matthew R D Cobain and Barry J. Everitt and Angus Murray Macleod and Hedaythul I Choudhury and Louise M. McDonald and Goplan V Pillai and W. Stanley Rycroft and A. J. Smith and Francine Sternfeld and F. David Tattersall and Keith A. Wafford and David S. Reynolds and Guy R. Seabrook and J. R. Atack},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2006},
  volume={316},
  pages={1335 - 1345}
}
  • G. Dawson, K. Maubach, J. Atack
  • Published 1 March 2006
  • Biology, Psychology
  • Journal of Pharmacology and Experimental Therapeutics
α5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABAA receptors containing an α1, α2, α3, or α5 subunit but has inverse agonist efficacy selective for the α5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABAA receptors containing an α5 subunit. In a mouse hippocampal slice model, α5IA significantly enhanced the θ burst-induced long-term potentiation of the excitatory postsynaptic… 

Figures and Tables from this paper

RO4938581, a novel cognitive enhancer acting at GABAA α5 subunit-containing receptors
TLDR
RO4938581 is a potent inverse agonist at the GABAA α5 receptor, with both binding and functional selectivity, enhancing hippocampal LTP, and further support the potential of GAB AA α5 receptors as a target for cognition-enhancing drugs.
Preclinical and clinical pharmacology of the GABAA receptor alpha5 subtype-selective inverse agonist alpha5IA.
  • J. Atack
  • Biology, Medicine
    Pharmacology & therapeutics
  • 2010
GABAA Receptor α2/α3 Subtype-Selective Modulators as Potential Nonsedating Anxiolytics
TLDR
Data indicate that the pharmacological profile of compounds that differentially modulate specific populations of GABAA receptors is distinct from classical benzodiazepines and should encourage further preclinical and clinical investigation of such compounds, with the caveat that, as exemplified by MRK-409, the preclinical profile might not necessarily translate into man.
Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice
TLDR
It is demonstrated that α5IA restores learning and memory functions of Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks and enhances learning-evoked immediate early gene products in specific brain regions involved in cognition following behavioural stimulation.
An inverse agonist selective for α5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze
TLDR
These data further highlight the cognition-enhancing properties of GABAA α5-selective inverse agonists and define the functional specificity of these effects in terms of encoding and recall processes in the Morris water maze.
Selective Modulators of α5-Containing GABAA Receptors and their Therapeutic Significance.
TLDR
A review of the various positive and negative modulators for 5GABAARs that have been developed, key findings concerning their effects in behavioral studies, and their importance across a number of therapeutic fields are highlighted.
Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist
TLDR
TPA023B was well tolerated at a dose that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABAA receptor population for avoiding sedation in man.
MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans
TLDR
The data show that MRK-409 causes sedation in humans at a dose corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 65 REFERENCES
Trace fear conditioning involves hippocampal α5 GABAA receptors
  • F. Crestani, R. Keist, U. Rudolph
  • Biology, Psychology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
TLDR
The largely extrasynaptic α5GABAA receptors in hippocampal pyramidal cells are implicated as control elements of the temporal association of threat cues in trace fear conditioning, which altered the drug-independent behavior of mutant mice.
Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes
GABAA (γ-aminobutyric acidA) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the
Effects of Hippocampal Injections of a Novel Ligand Selective for the α5β2γ2 Subunits of the GABA/Benzodiazepine Receptor on Pavlovian Conditioning
TLDR
RY024 independently produced fear-related behavior prior to training and, at the highest concentration, decreased the strength of conditioning observed 24 h after training, providing further evidence for the involvement of hippocampal GABAA/benzodiazepine receptors in learning and anxiety.
Anxiogenic properties of an inverse agonist selective for α3 subunit‐containing GABAA receptors
TLDR
The data demonstrate that an inverse agonist selective for GABAA receptors containing an α3 subunit is anxiogenic, and suggest that since α3‐containing GAB AA receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.
Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the α5 Subunit of the GABAAReceptor
TLDR
Data suggest that α5-containing GABAA receptors play a key role in cognitive processes by controlling a component of synaptic transmission in the CA1 region of the hippocampus.
Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics.
TLDR
The point-mutated knockin mice in which specific GABAA receptor sub types are insensitive to diazepam or some general anesthetics have revealed the specific contribution of individual receptor subtypes to the pharmacological spectrum of diazepAM and general anESThetics.
Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype
TLDR
This work created genetically modified mice with a diazepam-insensitive α1 subtype and a selective BZ site ligand to explore GABAA receptor subtypes mediating specific physiological effects and revealed that the α1Subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines.
...
1
2
3
4
5
...