Identification of simple substituted phenols with thyromimetic activity: Cardiac effects of 3,5-diiodo-4-hydroxyphenylpropionic acid

To define the minimal structural requirements for cardiac activity of thyroid hormone analogs, a series of substituted phenols were screened for their ability to bind bacterially expressed thyroid hormone receptors. Compounds with binding activity then were tested for their ability to induce expression of alpha-myosin heavy chain mRNA in primary cultures of fetal rat cardiomyocytes, a sensitive marker for potential inotropic activity. 3,5- Diiodo-4-hydroxyphenylpropionic acid (DIHPA) was found to bind specifically to bacterially expressed alpha-1 and beta-1 thyroid hormone receptors (K(aff) ≃ 1 to 2 x 10⁵ M^-1) and to induce alpha-myosin heavy chain (EC₅₀ ≃ 5 x 10^-7). To assess the effects of DIHPA on cardiac performance in vivo, hemodynamic measurements were made in three groups of hypothyroid rats treated for 5 days with s.c. doses of DIHPA (15 mg/100 g), L-thyroxine (T₄, 1.5 μg/100 g) or saline. Compared to controls, DIHPA and T₄ produced increases in heart rate, left ventricular +dP/dT(max), -dP/dT(max), and isovolumic relaxation. In isometric papillary muscles preparations, DIHPA and T₄ shortened time-to-peak tension and time-from-peak tension to 50% decline as compared with saline-treated controls. Muscles from both drug-treatment groups showed similar responses to graded doses of isoproterenol (10^-8 to 10^-3 M) and to variations in Ca⁺⁺ concentration of the muscle bath (0.3125 to 3.75 x 10^-3 M). Thus, DIHPA is a novel thyromimetic compound with effects on myocardial function similar to those observed with T₄.