Benson M G, Ellis D, Emmett J C, Leeson P D, Pearce N J, Shah V P, Underwood A H
Biochem Pharmacol. 1984 Oct 15;33(20):3143-9. doi: 10.1016/0006-2952(84)90070-4.
The 4'-phenolic hydroxyl group of thyroid hormones plays an important role in receptor binding, and it has been suggested that the interaction of this hydroxyl group with the receptor involves hydrogen bonding via donation of the acidic hydrogen in a trans disposition to the 3'-substituent of the hormones. In order to test this hypothesis we have synthesised, and measured the hepatic receptor affinity and thyromimetic activity of 3'-acetyl-3,5-diiodo-L-thyronine (3'-Ac-T2), a compound in which the formation of such a receptor-phenol hydrogen bond is precluded by the presence of a strong intramolecular hydrogen bond between the 3'-acetyl- and 4'-hydroxyl groups. In confirmation of the hypothesis, 3'-Ac-T2 has a low affinity (0.5% of that of 3,5,3'-triiodo-L-thyronine, T3) for the T3-receptor in isolated rat hepatic nuclei. By contrast the thyromimetic activity (assessed by its ability to induce rat hepatic glycerol-3-phosphate dehydrogenase and increase the qO2 of liver slices) was roughly equal to that of T3. This apparent discrepancy was resolved when it was found that the capacity of 3'-Ac-T2 to occupy hepatic receptors after in vivo administration, was about 100 times greater than predicted from its in vitro affinity. The reason for this difference between in vivo and in vitro nuclear binding is unknown at the present time.
甲状腺激素的4'-酚羟基在受体结合中起重要作用，有人提出该羟基与受体的相互作用涉及通过将酸性氢以反式构型提供给激素的3'-取代基来形成氢键。为了验证这一假设，我们合成了3'-乙酰基-3,5-二碘-L-甲状腺原氨酸（3'-Ac-T2），并测量了其肝受体亲和力和拟甲状腺活性。在该化合物中，3'-乙酰基和4'-羟基之间存在强分子内氢键，从而排除了这种受体-酚氢键的形成。为证实该假设，3'-Ac-T2对分离的大鼠肝细胞核中的T3受体具有低亲和力（为3,5,3'-三碘-L-甲状腺原氨酸，即T3的0.5%）。相比之下，其拟甲状腺活性（通过其诱导大鼠肝甘油-3-磷酸脱氢酶和增加肝切片qO2的能力来评估）与T3大致相当。当发现3'-Ac-T2在体内给药后占据肝受体的能力比根据其体外亲和力预测的大100倍左右时，这一明显差异得到了解释。目前尚不清楚体内和体外核结合之间这种差异的原因。
