Conformation of thyroid hormone analogues

COMPARISON of the activities of conformationally ‘fixed’ derivatives of thyroid hormones has led to the proposal that the active conformation of 3,5,3′-triiodo-L-thyronine (L-T 3 ) is one in which the 3′-iodine is distal to the inner (α) ring 1–4 (Fig. 1). These conclusions have prompted several X-ray studies aimed at determining the conformational preference in the crystals of thyroid hormones 5–10 . Such studies have shown that the positioning of the 3′-iodine in the crystal structures of L-T 3 and related compounds is dependent on the crystallising medium, thus suggesting that the distal and proximal forms of L-T 3 are of similar energy. These findings prompted us to investigate the temperature dependence of the proton nuclear magnetic resonance (NMR) spectra of thyroid hormone analogues to determine, in solution, both the magnitude of the barrier to rotation around the ether oxygen and, in unsymmetrical molecules, the relative populations of distal and proximal forms.