Lin Linus S, Ha Sookhee, Ball Richard G, Tsou Nancy N, Castonguay Laurie A, Doss George A, Fong Tung M, Shen Chun-Pyn, Xiao Jing Chen, Goulet Mark T, Hagmann William K
Departments of Medicinal Chemistry, Molecular Systems, Process Research, and Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA.
J Med Chem. 2008 Apr 10;51(7):2108-14. doi: 10.1021/jm7014974. Epub 2008 Mar 12.
X-ray crystallographic, NMR spectroscopic, and computational studies of taranabant afforded similar low-energy conformers with a significant degree of rigidity along the C11-N13-C14-C16-C17 backbone but with more flexibility around bonds C8-C11 and C8-O7. Mutagenesis and docking studies suggested that taranabant and rimonabant shared the same general binding area of CB1R but with significant differences in detailed interactions. Similar to rimonabant, taranabant interacted with a cluster of aromatic residues (F(3.36)200, W(5.43)279, W(6.48)356, and Y(5.39)275) through the two phenyl rings and with F(2.57)170 and L(7.42)387 through the CF 3-Pyr ring. The notable distinction between taranabant and rimonabant was that taranabant was hydrogen-bonded with S(7.39)383 but not with K(3.28)192, while rimonabant was hydrogen-bonded with K(3.28)192 but not with S(7.39)383. The strong hydrogen bonding between the amide NH of taranabant and hydroxyl of S(7.39)383 was key to the superior affinity of taranabant to CB1R.
对taranabant的X射线晶体学、核磁共振光谱学和计算研究表明，其具有相似的低能量构象异构体，沿C11-N13-C14-C16-C17主链具有显著的刚性，但在C8-C11和C8-O7键周围具有更大的灵活性。诱变和对接研究表明，taranabant和利莫那班共享CB1R相同的一般结合区域，但在详细相互作用方面存在显著差异。与利莫那班类似，taranabant通过两个苯环与一组芳香族残基（F(3.36)200、W(5.43)279、W(6.48)356和Y(5.39)275）相互作用，并通过CF 3-吡啶环与F(2.57)170和L(7.42)387相互作用。taranabant和利莫那班之间的显著区别在于，taranabant与S(7.39)383形成氢键，但不与K(3.28)192形成氢键，而利莫那班与K(3.28)192形成氢键，但不与S(7.39)383形成氢键。taranabant的酰胺NH与S(7.39)383的羟基之间的强氢键是taranabant对CB1R具有卓越亲和力的关键。
