Pharmacological profile of the thyroid hormone receptor antagonist NH3 in rats

NH3 is a thyroid hormone receptor ( TR) antagonist that inhibits binding of thyroid hormones to their receptor and that inhibits cofactor recruitment. It was active in a tadpole tail resorption assay, with partial agonist activity at high concentrations. We determined the effect of NH3 on the cholesterol- lowering, thyroid stimulating hormone ( TSH)- lowering, and tachycardic action of thyroid hormone ( T-3) in rats. Cholesterol- fed, euthyroid rats were treated for 7 days with NH3, and a dose response ( 46.2 - 27,700 nmol/ kg/ day) was determined. We also determined the effect of two doses of T-3 on the NH3 dose- response curve. NH3 decreased heart rate modestly starting at 46.2 nmol/ kg/ day, but the effect was lost at > 2920 nmol/ kg/ day. At 27,700 nmol/ kg/ day, tachycardia was seen, suggesting partial agonist activity. NH3 increased plasma cholesterol to a maximum of 27% at 462 nmol/ kg/ day. At higher doses, cholesterol was reduced, suggesting partial agonist activity. Plasma TSH was increased from 46.2 to 462 nmol/ kg/ day NH3, but at higher doses, this effect was lost, and partial agonist effects were apparent. T-3 at 15.4 and 46.2 nmol/ kg/ day increased heart rate, reduced cholesterol, and reduced plasma TSH. NH3 inhibited the cholesterol- lowering, TSH- lowering and tachycardic effects of 15.4 nmol/ kg/ day T-3, but much of the effect was lost at > 924 nmol/ kg/ day doses. NH3 had no effect on the cholesterol-lowering action of 46.2 nmol/ kg/ day T-3, but it inhibited the tachycardic and TSH suppressant effects up to the 924 nmol/ kg/ day dose. Single doses of 462 and 27,700 nmol/ kg caused no TR inhibitory effects. In conclusion, NH3 has TR antagonist properties on T-3-responsive parameters, but it has partial agonist properties at higher doses.