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Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors.

Publication ,  Journal Article
Petroski, RE; Pomeroy, JE; Das, R; Bowman, H; Yang, W; Chen, AP; Foster, AC
Published in: J Pharmacol Exp Ther
April 2006

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 GABA(A) receptors from rat brain and acts as a positive allosteric modulator of GABA(A) receptor currents in cultured rat neurons (Sullivan et al., 2004). In this study, we examined the GABA(A) receptor alpha subunit selectivity of indiplon using electrophysiological techniques to record GABA-activated chloride currents from recombinant rodent GABA(A) receptors expressed in human embryonic kidney 293 cells. Indiplon potentiated the GABA-activated chloride current in recombinant GABA(A) receptors in a dose-dependent and reversible manner and was approximately 10-fold selective for alpha1 subunit-containing receptors over GABA(A) receptors containing alpha2, alpha3, or alpha5 subunits. The EC(50) values were 2.6, 24, 60, and 77 nM for alpha1beta2gamma2, alpha2beta2gamma2, alpha3beta3gamma2, and alpha5beta2gamma2 receptors, respectively. Indiplon was approximately 10 times more potent than zolpidem and zopiclone and >100 times more potent than zaleplon. Moreover, indiplon, up to 1 microM, did not potentiate GABA(A) receptors composed of alpha4beta2gamma2 and alpha6beta2gamma2 subunits. This mechanism of action is proposed to underlie the sedative-hypnotic effects of indiplon in animals and humans.

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Published In

J Pharmacol Exp Ther

DOI

ISSN

0022-3565

Publication Date

April 2006

Volume

317

Issue

1

Start / End Page

369 / 377

Location

United States

Related Subject Headings

  • Thiophenes
  • Recombinant Proteins
  • Receptors, GABA-A
  • Rats
  • Protein Subunits
  • Pharmacology & Pharmacy
  • Neurons
  • Molecular Structure
  • Hypnotics and Sedatives
  • Humans
 

Citation

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Petroski, R. E., Pomeroy, J. E., Das, R., Bowman, H., Yang, W., Chen, A. P., & Foster, A. C. (2006). Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. J Pharmacol Exp Ther, 317(1), 369–377. https://doi.org/10.1124/jpet.105.096701
Petroski, Robert E., Jordan E. Pomeroy, Ronnie Das, Heath Bowman, Weidong Yang, Adele P. Chen, and Alan C. Foster. “Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors.J Pharmacol Exp Ther 317, no. 1 (April 2006): 369–77. https://doi.org/10.1124/jpet.105.096701.
Petroski RE, Pomeroy JE, Das R, Bowman H, Yang W, Chen AP, et al. Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. J Pharmacol Exp Ther. 2006 Apr;317(1):369–77.
Petroski, Robert E., et al. “Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors.J Pharmacol Exp Ther, vol. 317, no. 1, Apr. 2006, pp. 369–77. Pubmed, doi:10.1124/jpet.105.096701.
Petroski RE, Pomeroy JE, Das R, Bowman H, Yang W, Chen AP, Foster AC. Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. J Pharmacol Exp Ther. 2006 Apr;317(1):369–377.

Published In

J Pharmacol Exp Ther

DOI

ISSN

0022-3565

Publication Date

April 2006

Volume

317

Issue

1

Start / End Page

369 / 377

Location

United States

Related Subject Headings

  • Thiophenes
  • Recombinant Proteins
  • Receptors, GABA-A
  • Rats
  • Protein Subunits
  • Pharmacology & Pharmacy
  • Neurons
  • Molecular Structure
  • Hypnotics and Sedatives
  • Humans