Design and Synthesis of D[sub.3]R 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 D[sub.3]R-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...

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Veröffentlicht in:Molecules (Basel, Switzerland) Switzerland), 2023-12, Vol.29 (1)
Hauptverfasser: Tian, Gui-Long, Hsieh, Chia-Ju, Taylor, Michelle, Lee, Ji Youn, Luedtke, Robert R, Mach, Robert H
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container_title Molecules (Basel, Switzerland)
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creator Tian, Gui-Long
Hsieh, Chia-Ju
Taylor, Michelle
Lee, Ji Youn
Luedtke, Robert R
Mach, Robert H
description 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]R-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 ASP110[sup.3.32] of the D[sub.3]R, thereby reducing the D[sub.3]R affinity to a suboptimal level.
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subjects Antiparkinsonian agents
Dopamine receptors
Nervous system diseases
Schizophrenia
title Design and Synthesis of D[sub.3]R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies
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