Structural requirements for maximal inhibitory allosteric effect of estrogens and estrogen analogues on glutamate dehydrogenase.

The inhibition of glutamate dehydrogenase by estrogens, estrogen analogues or polyphenylethylene derivatives (about one hundred molecules, most of them having estrogenic or antiestrogenic activities) was measured. The efficiency of these compounds in inducing allosteric inhibition of the enzyme was compared and correlated to their chemical structure: an aromatic ring A, a free phenolic group in the region of carbon 3 of the steroid nucleus and a lipophilic substitution in the region of C-12, C-13 or C-17 were found to be the main structural features required for maximal efficiency on glutamate dehydrogenase. A tentative model for the relative orientation of the main inhibitor families is proposed. It accounts for most of the kinetic results and can be used as a tool for the selection of affinity labels directed towards the estrogen binding site of glutamate dehydrogenase.