Design and Synthesis of D3R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies

A series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D3R-selective compound. The effect of the flexible linker ((R,S)-trans-2a–d), SBFs ((R,S)-trans-2h–j), and the chirality of orthosteric binding fragments (OBFs)...

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Published inMolecules (Basel, Switzerland) Vol. 29; no. 1; p. 123
Main Authors Tian, Gui-Long, Hsieh, Chia-Ju, Taylor, Michelle, Lee, Ji Youn, Luedtke, Robert R., Mach, Robert H.
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 01.01.2024
MDPI
Subjects
Binding sites
bitopic ligands
Carbon
Competition
Dopamine
dopamine 2 receptor
dopamine 3 receptor
flexible linker
Ligands
molecular dynamic simulation
Nitrogen
Polyethylene glycol
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Summary:A series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D3R-selective compound. The effect of the flexible linker ((R,S)-trans-2a–d), SBFs ((R,S)-trans-2h–j), and the chirality of orthosteric binding fragments (OBFs) ((S,R)-trans-d, (S,R)-trans-i, (S,S)-trans-d, (S,S)-trans-i, (R,R)-trans-d, and (R,R)-trans-i) 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 ASP1103.32 of the D3R, thereby reducing the D3R affinity to a suboptimal level.
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content type line 23
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ISSN:1420-3049
1420-3049
DOI:10.3390/molecules29010123