Limiting Activity at β1-Subunit-Containing GABAA Receptor Subtypes Reduces Ataxia

@article{Gee2010LimitingAA,
  title={Limiting Activity at $\beta$1-Subunit-Containing GABAA Receptor Subtypes Reduces Ataxia},
  author={Kelvin W. Gee and Minhtam B. Tran and Derk J. Hogenkamp and Timothy B C Johnstone and Rudy E Bagnera and Ryan F. Yoshimura and Jin-Cheng Huang and James D. Belluzzi and Edward R. Whittemore},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2010},
  volume={332},
  pages={1040 - 1053}
}
GABAA receptor (R) positive allosteric modulators that selectively modulate GABAARs containing β2- and/or β3- over β1-subunits have been reported across diverse chemotypes. Examples include loreclezole, mefenamic acid, tracazolate, and etifoxine. In general,“β2/3-selective” GABAAR positive allosteric modulators are nonbenzodiazepines (nonBZs), do not show α-subunit isoform selectivity, yet have anxiolytic efficacy with reduced ataxic/sedative effects in animal models and humans. Here, we report… 
Limited central side effects of a β-subunit subtype-selective GABAA receptor allosteric modulator
TLDR
Results suggest that β2/3-subunit subtype-selective GABAA receptor-positive allosteric modulators not only have reduced sedative liability, but also a reduction in other central side effects commonly associated with broader GabAA receptor activation.
Positive allosteric modulators of nonbenzodiazepine &ggr;-aminobutyric acidA receptor subtypes for the treatment of chronic pain
TLDR
2-261 may produce pain relief with diminished side effects through selective modulation of &bgr;2/3-subunit–containing extrasynaptic GABAARs.
Pharmacological characterisation of murine α4β1δ GABAA receptors expressed in Xenopus oocytes
TLDR
The first pharmacological characterisation of various GABAA receptor ligands acting at murine α4β1δ GAB AA receptors is reported, thereby improving the understanding of the molecular pharmacology of this receptor isoform.
Design, Synthesis, and Pharmacological Evaluation of Novel β2/3 Subunit-Selective γ-Aminobutyric Acid Type A (GABAA) Receptor Modulators.
TLDR
Compound 12 constitutes a novel, simplified, and subunit-selective GABAAR modulator with low-dose anticonvulsant activity and in vivo studies revealed significantly more potent protection against pentylenetetrazole (PTZ)-induced seizures compared to VA and LOR.
α4βδ GABAA receptors are high-affinity targets for γ-hydroxybutyric acid (GHB)
TLDR
The authors' data link specific GHB forebrain binding sites with α4-containing GABAA receptors and postulate a role for extrasynaptic α4δ-containing GHB receptors in GHB pharmacology and physiology to aid in elucidating the molecular mechanisms behind the proposed function of GHB as a neurotransmitter and its unique therapeutic effects in narcolepsy and alcoholism.
Allosteric modulation of nicotinic and GABAA receptor subtypes differentially modify autism-like behaviors in the BTBR mouse model
International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans
TLDR
An up-to-date review on the currently available GABAA receptor subtype-selective ligands and proposals for the future development of ligands with better anxioselectivity in humans are made.
...
1
2
3
4
...

References

SHOWING 1-10 OF 55 REFERENCES
Nootropic α7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators
TLDR
A selective α7 nAChR-positive allosteric modulator (PAM) from a library of GABAA receptor PAMs is generated, which corrects sensory-gating deficits and improves working memory, effects consistent with cognitive enhancement in rodent models.
Subunit‐selective modulation of GABAA receptors by the non‐steroidal anti‐inflammatory agent, mefenamic acid
TLDR
Molecular comparisons of MFA, loreclezole and etomidate, agents which exhibit similar selectivity for GABAA receptors, revealed their ability to adopt similar structural conformations and indicates that N290 in TM2 of β2 and β3 subunits is important for the regulation of GAB AA receptor function by MFA.
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
Compounds Exhibiting Selective Efficacy for Different β Subunits of Human Recombinant γ-Aminobutyric AcidA Receptors
TLDR
This study identifies and characterizes a variety of allosteric modulators for which βsubunits are an important determinant of efficacy and potency, and describes the anti-inflammatories exhibited varying levels of efficacy at β2/3 subunits, with micromolar potency, while having antagonist or weak inverse agonist profiles at α1β1γ2.
The role of GABAAβ2 subunit‐containing receptors in mediating the anticonvulsant and sedative effects of loreclezole
TLDR
The results suggest that the majority of the sedative effects and a significant proportion of the anticonvulsant efficacy of loreclezole are mediated via β2‐containing GABAA receptors.
Compounds exhibiting selective efficacy for different beta subunits of human recombinant gamma-aminobutyric acid A receptors.
TLDR
A variety of allosteric modulators are identified and characterizes for which betasubunits are an important determinant of efficacy and potency, and several compounds displayed beta2/3 subunit selectivity, notably loreclezole, R(-)-etomidate, and a group of anti-inflammatory agents.
Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.
GABA(A) (gamma-aminobutyric acid(A)) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from
Subunit‐dependent interaction of the general anaesthetic etomidate with the γ‐aminobutyric acid type A receptor
TLDR
It is concluded that the subtype of β‐subunit influences the potency with which etomidate potentiates GABA‐evoked currents and that the β isoform is a crucial determinant of the GABA‐mimetic activity of this compound.
Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABAA α2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers
TLDR
Although less effect on VAs alertness was expected, diminished effects on memory and postural stability were present and clinical studies in anxiety patients should show whether this dose of MK-0343 is therapeutically effective with a different side-effect profile.
...
1
2
3
4
5
...