Inhibition of the activity of the native gamma-aminobutyric acid A receptor by metabolites of thyroid hormones: correlations with molecular modeling studies.

To characterize the direct effects of thyroid hormones on native gamma-aminobutyric acid(A) (GABA(A)) receptors, rapid (5 s) actions of a series of iodothyronines on muscimol-stimulated uptake of (36)Cl(-) were investigated in synaptoneurosomes prepared from rat brain. The results were correlated with molecular modeling of the active compounds. Dose-response curves for muscimol in the presence of 3,3', 5-L-triiodothyronine (L-T3) indicated a noncompetitive inhibition of muscimol-stimulated (36)Cl(-) uptake by the thyroid hormone. Synaptoneurosomes prepared from cerebellum were less sensitive to L-T3 than those from cerebral cortex, in terms of the potency of the hormone. The overall efficacy approached complete inhibition for both brain regions. Muscimol-stimulated (36)Cl(-) uptake was inhibited differentially by iodothyronine derivatives. One group of compounds with IC(50) values of 18-30 microM included L-thyroxine (L-T4), D-thyroxine (D-T4), 3,3', 5,5'-tetraiodothyroacetic acid (Tetrac), and 3,3', 5-triiodothyroacetic acid (Triac). A second group with values of 75-100 microM included 3,3', 5'-l-triiodothyronine (reverse T3; r-T3), 3,3'-diiodo-L-thyronine (3,3'-l-T2) and 3,5-diiodo-L-thyronine (3,5-D-T2). A final group of inactive compounds with IC(50) values greater than 100 microM included 3',5'-diiodo-L-thyronine (3',5'-l-T2), 3-iodo-L-thyronine (L-T1), 3'-iodo-L-thyronine (3'-L-T1), and L-thyronine (L-T0). Molecular modeling of the active iodothyronines using the Gaussian03 series of programs indicated close correspondences with models of the GABA-inhibitory neurosteroid pregnenolone sulfate (PREGS), suggesting common mechanisms of action at the GABA(A) receptor.