Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors.

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Wingrove PB, Safo P, Wheat L, Thompson SA, Wafford KA, Whiting PJ

Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors.

Eur J Pharmacol. 2002 Feb 15;437(1-2):31-9.

PubMed ID

11864636 [ View in PubMed

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Abstract

Benzodiazepine pharmacology at the GABA(A) receptor is dependent on the alpha and gamma subunit isoforms present. Ligands with higher affinity for certain isoforms--selective compounds--have been classified into benzodiazepine type I and II and into diazepam-sensitive and diazepam-insensitive receptors. A single amino acid position (alpha1G201/alpha3E225) has been identified which discriminates BZI and BZII receptors. The role of this residue has been explored by mutagenesis of alpha1 position 201 and the pharmacology of recombinant receptors examined using BZI receptor agonists. Ligand affinity is reduced by increasing side chain volume at alpha1G201 suggesting that steric inhibition underlies alpha-subunit selectivity. A second amino acid (alpha1H102/alpha6R100) determines diazepam sensitivity. The nature of the amino acid at this position was also examined by mutagenesis. Flumazenil and Ro15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carboxyl ate) binding affinity correlated weakly with the amino acid hydrophobicity suggesting a weak hydrophobic interaction between the ligand and alpha1H102.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Flumazenil	Gamma-aminobutyric acid receptor subunit alpha-1	Protein	Humans	Yes	Antagonist	Details
Flumazenil	Gamma-aminobutyric acid receptor subunit gamma-2	Protein	Humans	Yes	Antagonist	Details