Biomedical subjects

Hikari A I Yoshihara

Publications and source records attributed to Hikari A I Yoshihara.

3 recordsLinked to original sources

PubMed2003

Structural determinants of selective thyromimetics.

The thyromimetic GC-1 shows a preference for binding the beta form of the thyroid hormone receptor (TR). GC-1 was designed as an analogue of the thyromimetic DIMIT, which has a lower affinity for TR and is not selective. GC-1 has a methylene group linking its two aromatic rings and an oxyacetic acid polar side chain, while DIMIT has an ether oxygen linking its aromatic rings and an l-alanine polar side chain. The structural features of GC-1 that confer its greater affinity and selectivity compared to DIMIT were analyzed with the preparation of analogues that bear only one of their two different structural features. The analogue of GC-1 with a biaryl ether has selectivity comparable to that of GC-1, while the analogue of DIMIT with a methylene group linking its aromatic rings is only slightly selective. These results demonstrate that the oxyacetic acid side chain of GC-1 is critical in conferring TR-beta selectivity.

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PubMed2003

Selective thyroid hormone receptor modulators.

Thyroid hormone regulates many important processes in vertebrates. Analysis of the symptoms that accompany hypo- and hyperthyroidism, the most common disorders of the thyroid, suggests that there are certain desirable biological effects brought about by an excess or deficiency of thyroid hormone, and that selective thyroid hormone receptor modulators (STRMs) would be potentially useful therapeutic agents. This review will provide an introduction to thyroid hormone biology, and will discuss the chemistry and pharmacology of the first generation STRMs.

Animals↗

PubMed2002

Design of thyroid hormone receptor antagonists from first principles.

It is desirable to obtain TR antagonists for treatment of hyperthyroidism and other conditions. We have designed TR antagonists from first principles based on TR crystal structures. Since agonist ligands are buried in the fold of the TR ligand binding domain (LBD), we reasoned that ligands that resemble agonists with large extensions should bind the LBD, but would prevent its folding into an active conformation. In particular, we predicted that extensions at the 5' aryl position of ligand should reposition helix (H) 12, which forms part of the co-activator binding surface, and thereby inhibit TR activity. We have found that some synthetic ligands with 5' aryl ring extensions behave as antagonists (DIBRT, NH-3), or partial antagonists (GC-14, NH-4). Moreover, one compound (NH-3) represents the first potent TR antagonist with nanomolar affinity that also inhibits TR action in an animal model. However, the properties of the ligands also reveal unexpected aspects of TR behavior. While nuclear receptor antagonists generally promote binding of co-repressors, NH-3 blocks co-activator binding and also prevents co-repressor binding. More surprisingly, many compounds with extensions behave as full or partial agonists. We present hypotheses to explain both behaviors in terms of dynamic equilibrium of H12 position.

Animals↗