Design and Synthesis of D(3)R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies

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dc.creatorTian, Gui-Long
dc.creatorHsieh, Chia-Ju
dc.creatorTaylor, Michelle
dc.creatorLee, Ji Youn
dc.creatorLuedtke, Robert R.
dc.creatorMach, Robert H.
dc.creator.orcid0000-0001-8469-2371 (Luedtke, Robert R.)
dc.date.accessioned2024-02-14T15:35:54Z
dc.date.available2024-02-14T15:35:54Z
dc.date.issued2024-01-11
dc.description.abstractA series of bitopic ligands based on Fallypride with a flexible secondary binding fragment (SBF) were prepared with the goal of preparing a D(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(3.32) of the D(3)R, thereby reducing the D(3)R affinity to a suboptimal level.
dc.description.sponsorshipThis work was supported by a grant from the National Institute on Drug Abuse, grant number DA029840.
dc.identifier.citationTian, G. L., Hsieh, C. J., Taylor, M., Lee, J. Y., Luedtke, R. R., & Mach, R. H. (2023). Design and Synthesis of D3R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies. Molecules (Basel, Switzerland), 29(1), 123. https://doi.org/10.3390/molecules29010123
dc.identifier.issn1420-3049
dc.identifier.issue1
dc.identifier.urihttps://hdl.handle.net/20.500.12503/32502
dc.identifier.volume29
dc.publisherMDPI
dc.relation.urihttps://doi.org/10.3390/molecules29010123
dc.rights.holder© 2023 by the authors.
dc.rights.licenseAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceMolecules
dc.subjectbitopic ligands
dc.subjectdopamine 2 receptor
dc.subjectdopamine 3 receptor
dc.subjectflexible linker
dc.subjectmolecular dynamic simulation
dc.subject.meshComputational Chemistry
dc.subject.meshNitrogen
dc.titleDesign and Synthesis of D(3)R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies
dc.typeArticle
dc.type.materialtext

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