Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, United States; Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, United States.
Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, United States.
Bioorg Med Chem Lett. 2021 Jun 15;42:128047. doi: 10.1016/j.bmcl.2021.128047. Epub 2021 Apr 18.
The effect of rigidification of the n-butyl linker region of tetrahydroisoquinoline-containing DR ligands via inclusion of an o-xylenyl motif was examined in this study. Generally, rigidification with an o-xylenyl linker group reduces DR affinity and negatively impacts selectivity versus DR for compounds possessing a 6-methoxy-1,2,3,4,-tetrahydroisoquinolin-7-ol primary pharmacophore group. However, DR affinity appears to be regulated by the primary pharmacophore group and high affinity DR ligands with 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline primary pharmacophore groups were identified. The results of this study also indicate that DR selectivity versus the σR is dictated by the benzamide secondary pharmacophore group, this being facilitated with 4-substituted benzamides. Compounds 5s and 5t were identified as high affinity (K < 4 nM) DR ligands. Docking studies revealed that the added phenyl ring moiety interacts with the Cys181 in DR which partially accounts for the strong DR affinity of the ligands.
本研究考察了通过包含邻二甲苯基基元使含四氢异喹啉的 DR 配体的正丁基连接区刚性化的效果。通常，用邻二甲苯基连接基团刚性化会降低 DR 亲和力，并对具有 6-甲氧基-1,2,3,4-四氢异喹啉-7-醇主要药效基团的化合物的选择性产生负面影响。然而，DR 亲和力似乎受主要药效基团调控，并且鉴定出具有 6,7-二羟基-1,2,3,4-四氢异喹啉和 6,7-二甲氧基-1,2,3,4-四氢异喹啉主要药效基团的高亲和力 DR 配体。本研究的结果还表明，DR 相对于 σR 的选择性由苯甲酰胺次要药效基团决定，这在 4-取代苯甲酰胺中得到促进。化合物 5s 和 5t 被鉴定为高亲和力（K < 4 nM）DR 配体。对接研究表明，添加的苯基环部分与 DR 中的 Cys181 相互作用，这部分解释了配体对 DR 的强亲和力。
