Substituted pyrazinones, a new class of allosteric modulators for gamma-aminobutyric acidA receptors.
We discovered substituted pyrazinones as a new class of allosteric modulators of gamma-aminobutyric acid (GABA)A receptors. Prototype pyrazinones, U-92813 [1-(furfuryl)-3,5-dichloro-6-phenylpyrazinone] and U-94863 [1-benzyl-3,5-dichloro-6-(2-chlorophenyl)pyrazinone], potentiated GABA-mediated Cl- currents in cloned GABAA receptors with certain subtype selectivity. The drugs markedly enhanced the GABA response in the alpha 1 beta 2 gamma 2 and alpha 1 beta 2 subtypes but not in the alpha 1 gamma 2 and beta 2 gamma 2 subtypes expressed in human kidney cells. The dose-response profile of U-94863 in the alpha 1 beta 2 subtype was largely indistinguishable from that in the alpha 1 beta 2 gamma 2 subtype, suggesting no critical role for the gamma 2 subunit in potentiation of the GABA response by the pyrazinones. The drugs also potentiated the GABA response in the alpha 3 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 subtypes, indicating their nonselectivity toward the alpha isotypes. With respect to subtype selectivity, the pyrazinones differ not only from ligands for benzodiazepine receptors, which interact only with the subtypes containing alpha beta gamma subunits, but also from barbiturates and neurosteroids, which interact with all the subtypes tested in this study. The unique binding site for U-92813 on GABAA receptors was confirmed by the insensitivity of its action to Ro 15-1788, a classical benzodiazepine antagonist, and by the additive nature of its agonistic activity with that of barbiturates and neurosteroids. With respect to the mechanism of potentiation, the pyrazinones are similar to the other allosteric modulators, in that they potentiate the GABA response more effectively at low GABA concentrations than at high GABA concentrations. We propose that substituted pyrazinones represent a novel class of allosteric modulators of GABAA receptors, with their binding site probably located between the alpha and beta subunits.
Upjohn Company, Kalamazoo, Michigan 49001.
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Judge
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Gammill
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Hamilton
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Carter
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Pregenzer
D000494:Allosteric Regulation; D001593:Benzyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D005663:Furans / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D011719:Pyrazines / Q000378:metabolism / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001593:Benzyl Compounds; D002712:Chlorides; D005663:Furans; D011719:Pyrazines; D011963:Receptors, GABA-A; C082809:1-furfuryl-3,5-dichloro-6-phenylpyrazinone; C082808:1-benzyl-3,5-dichloro-6-(2-chlorophenyl)pyrazinone; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid