Design and Synthesis of D<sub>3</sub>R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies
oleh: Gui-Long Tian, Chia-Ju Hsieh, Michelle Taylor, Ji Youn Lee, Robert R. Luedtke, Robert H. Mach
| Format: | Article |
|---|---|
| Diterbitkan: | MDPI AG 2023-12-01 |
Deskripsi
A series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D<sub>3</sub>R-selective compound. The effect of the flexible linker (<b>(<i>R</i></b>,<b><i>S</i>)<i>-trans</i>-2a</b>–<b>d</b>), SBFs (<b>(<i>R</i></b>,<b><i>S</i>)<i>-trans</i>-2h</b>–<b>j</b>), and the chirality of orthosteric binding fragments (OBFs) (<b>(<i>S</i></b>,<b><i>R</i>)<i>-trans</i>-d</b>, <b>(<i>S</i>,<i>R</i>)<i>-trans</i>-i</b>, <b>(<i>S</i></b>,<b><i>S</i>)<i>-trans</i>-d</b>, <b>(<i>S</i></b>,<b><i>S</i>)<i>-trans</i>-i, (<i>R</i></b>,<b><i>R</i>)<i>-trans</i>-d,</b> and <b>(<i>R</i></b>,<b><i>R</i>)<i>-trans</i>-i</b>) were evaluated in in vitro binding assays. Computational chemistry studies revealed that the interaction of the fragment binding to the SBF increased the distance between the pyrrolidine nitrogen and ASP110<sup>3.32</sup> of the D<sub>3</sub>R, thereby reducing the D<sub>3</sub>R affinity to a suboptimal level.