Inhibition of thyroid hormone uptake by calcium antagonists of the dihydropyridine class

A series of substituted 4-phenyl-1,4-dihydropyridines 2a-m was tested for their inhibitory effects on L-triiodothyronine (L-T3) uptake by human HepG2 hepatoma cells. The most potent compounds were the nitro-substituted derivatives 2,6-dimethyl-4-(4'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester (2m) and the well-known calcium antagonists nitrendipine (2k) and nifedipine (2j) with an uptake inhibition between 80.5 and 85.8% at an application dose of 10(-5) M. On the basis of a theoretical conformational analysis (ab initio MO theory, molecular mechanics, molecular dynamics) of the dihydropyridine derivatives, a unifying stereochemical concept was derived postulating an angular arrangement of the two rings where the phenyl ring of the calcium antagonists, which corresponds to the outer phenyl ring of the thyroid hormones, is bisecting the dihydropyridine ring as a prerequisite for inhibitory potency. This model includes also inhibitors of the N-phenylanthranilic acid type. The interaction of the calcium antagonists with transthyretin (TTR) is discussed in relation to thyroid hormones. The influence of hydrophobicity was estimated by the experimental determination of the 1-octanol/water partition coefficients.