Design and Synthesis of D<sub>3</sub>R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies
Gui-Long Tian,
Chia-Ju Hsieh,
Michelle Taylor,
Ji Youn Lee,
Robert R. Luedtke,
Robert H. Mach
Affiliations
Gui-Long Tian
Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Chia-Ju Hsieh
Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Michelle Taylor
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Ji Youn Lee
Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Robert R. Luedtke
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Robert H. Mach
Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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.
