Inhibition of the activity of the native γ-aminobutyric acid _A receptor by metabolites of thyroid hormones: Correlations with molecular modeling studies

To characterize the direct effects of thyroid hormones on native γ-aminobutyric acid_A (GABA_A) receptors, rapid (5 s) actions of a series of iodothyronines on muscimol-stimulated uptake of ³⁶Cl^- 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 ³⁶Cl^- 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 ³⁶Cl^- uptake was inhibited differentially by iodothyronine derivatives. One group of compounds with IC ₅₀ values of 18-30 μM 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 μM 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 IC₅₀ values greater than 100 μM 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.