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ENDOCRINE AND DIABETES

Pharmacological Profile of the Thyroid Hormone Receptor Antagonist NH3 in Rats

Department of Pharmacology, Eurofins Scientific-Product Safety Laboratories, Dayton, New Jersey (G.J.G., C.D., J.B., G.D., J.D., P.B.); Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon (T.S.S.); and Department of Pharmaceutical Chemistry, University of California, San Francisco, California (N.-H.N.)

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 (T₃) 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 T₃ 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. T₃ 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 T₃, 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 T₃, 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 T₃-responsive parameters, but it has partial agonist properties at higher doses.

Address correspondence to: Dr. Gary J. Grover, Eurofins Scientific-Product Safety Laboratories, 2394 Hwy. 130, Dayton, NJ 08810. E-mail: garygrover{at}productsafetylabs.com