Development of functional molecules for elucidation of the physiological roles of several nuclear receptors and their endogenous ligands.

Nuclear receptors and their endogenous ligands are involved in key biological functions, including development, homeostasis and metabolism, and functional molecules that can modulate receptor activities are of interest for basic research to elucidate the signaling pathways, as well as having potential therapeutic applications. Here, we summarize our recent work on the development of nuclear receptor ligands, focusing on thyroid hormone receptor (TR) antagonists, fluorescent ligands for progesterone receptors (PR), and inhibitors of histone methyltransferase (HMT). We have developed a series of potent TR antagonists bearing a thiazolidinedione group as a bioisoster of a polar amino acid group. Utilizing our library of fluorescent coumarin derivatives, we obtained a PR antagonist that exhibits fluorescence enhancement upon binding to PR. We also developed a series of HMT inhibitors based on the structure of adenosylmethionine (AdoMet), a cofactor in the methylation reaction, by introducing various alkylamino groups onto the nitrogen atom in place of the sulfur atom of AdoMet. Our compounds should be useful in functional analysis of these nuclear receptors and investigations of their signaling pathways.