Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, Japan.
J Med Chem. 2010 Aug 12;53(15):5813-26. doi: 10.1021/jm100649d.
We previously reported that 22S-butyl-25,26,27-trinor-1alpha,24-dihydroxyvitamin D(3) 2 was a potent VDR antagonist. The X-ray crystal structure of the ligand binding domain of VDR complexed with 2 indicated that this ligand induces an extra cavity within the ligand-binding pocket. The structure also showed that the ligand forms only poor hydrophobic interactions with helix 12 of the protein. Here, to study the effects of the induction of the extra cavity and of insufficient interactions with helix 12 on antagonism, we designed and synthesized a series of vitamin D(3) analogues with or without a 22-alkyl substituent and evaluated their biological potency. We found that the 22-butyl analogues 3c and 5c act as full antagonists, the 22-ethyl analogues 3b, 4b, 5b, and 22-butyl analogue 4c act as partial agonists, and the others (3a, 4a, 5a, 6a, 6b, and 6c) act as full agonists for VDR. It is intriguing that 6c is a potent agonist for VDR, whereas its 26,27-dinor analogue 5c is a potent antagonist. Analogue 6c recruited coactivator SRC-1 well, but 5c did not. These results indicate that a combination of induction of the extra cavity and insufficient hydrophobic interactions with helix 12 is important for VDR antagonism in this class of ligands.
我们之前报道过，22S-丁基-25,26,27-三降-1α,24-二羟基维生素 D(3)2 是一种有效的 VDR 拮抗剂。与 VDR 结合的配体结合域的 X 射线晶体结构表明，该配体在配体结合口袋内诱导了一个额外的空腔。该结构还表明，该配体与蛋白质的螺旋 12 仅形成较差的疏水相互作用。在这里，为了研究诱导额外空腔和与螺旋 12 不足的相互作用对拮抗作用的影响，我们设计并合成了一系列具有或不具有 22-烷基取代基的维生素 D(3)类似物，并评估了它们的生物学效力。我们发现，22-丁基类似物 3c 和 5c 作为完全拮抗剂，22-乙基类似物 3b、4b、5b 和 22-丁基类似物 4c 作为部分激动剂，而其他类似物（3a、4a、5a、6a、6b 和 6c）作为 VDR 的完全激动剂。有趣的是，6c 是 VDR 的有效激动剂，而其 26,27-降维类似物 5c 是有效的拮抗剂。类似物 6c 很好地募集了共激活剂 SRC-1，但 5c 没有。这些结果表明，在这类配体中，诱导额外空腔和与螺旋 12 不足的疏水相互作用的组合对于 VDR 拮抗作用很重要。
