Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for α1 Subunit-Containing GABAA Receptors

@article{Petroski2006IndiplonIA,
  title={Indiplon Is a High-Affinity Positive Allosteric Modulator with Selectivity for $\alpha$1 Subunit-Containing GABAA Receptors},
  author={Robert E. Petroski and Jordan E. Pomeroy and Ronnie Das and Heath Bowman and Weidong Yang and Adele Pin Chen and Alan Carl Foster},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2006},
  volume={317},
  pages={369 - 377}
}
Indiplon (NBI 34060) is a novel pyrazolopyrimidine currently in development for the treatment of insomnia. We have previously shown that indiplon exhibits high-affinity binding to native GABAA receptors from rat brain and acts as a positive allosteric modulator of GABAA receptor currents in cultured rat neurons (Sullivan et al., 2004). In this study, we examined the GABAA receptor α subunit selectivity of indiplon using electrophysiological techniques to record GABA-activated chloride currents… 

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References

SHOWING 1-10 OF 50 REFERENCES

A single histidine in GABAA receptors is essential for benzodiazepine agonist binding.

Characterization of the Interaction of Indiplon, a Novel Pyrazolopyrimidine Sedative-Hypnotic, with the GABAA Receptor

In “GABA shift” experiments and in measurements of GABA-induced chloride conductance in rat cortical neurons in culture, indiplon behaved as an efficacious potentiator of GABAA receptor function, and in both the radioligand binding and electrophysiological experiments,Indiplon had a higher affinity than zolpidem or zaleplon.

Molecular Actions of (S)-Desmethylzopiclone (SEP-174559), an Anxiolytic Metabolite of Zopiclone

  • M. Fleck
  • Biology, Chemistry
    Journal of Pharmacology and Experimental Therapeutics
  • 2002
Assessment of the activity of (S)-desmethylzopiclone at subtypes of the γ-aminobutyric acid type-A (GABAA) receptor and other neurotransmitter receptor ion channels confirms that SEP-174559 has benzodiazepine-like actions at γ2-bearing sub types of the GABAA receptor and suggest additional actions of benzodiazine-site ligands at nACh and NMDA receptors.

The selectivity of zolpidem and alpidem for the α 1-subunit of the GABAA receptor

Zaleplon displays a selectivity to recombinant GABAA receptors different from zolipdem, zopiclone and benzodiazepines

The in vitro binding properties of the BZs lorazepam and Ro 15-4513 plus the three hypnotics zaleplon, zolpidem and zopiclone plus the α1βjγ2 receptor subtype may be the main mediator of the hypnotic properties of BZ receptor ligands.

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

Four Amino Acids in the α Subunits Determine the γ-Aminobutyric Acid Sensitivities of GABAA Receptor Subtypes*

Using both radioligand binding and electrophysiology combined with mutagenesis, a domain of four amino acids within the α subunits that mediates the distinct sensitivities to GABA is identified allowing their selective switch between αβ3γ2 combinations.

Comparison of the effects of zaleplon, zolpidem, and triazolam at various GABA(A) receptor subtypes.

Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs.

The results show that removal of either alpha1 or beta2 subunits of GABAA receptors produce strong and selective decreases in hypnotic effects of different drugs, confirming the crucial role of the GAB AA receptor in mechanisms mediating sedative/hypnotic effects.