Robert Luedtke, Ph.D.
Permanent URI for this communityhttps://hdl.handle.net/20.500.12503/31549
Member, Institute for Healthy Aging
Professor, Pharmacology & Neuroscience
Email: Robert.Luedtke@unthsc.edu
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Browsing Robert Luedtke, Ph.D. by Author "Hsieh, Chia-Ju"
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Item Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D(3)-Selective Antagonists(MDPI, 2023-01-09) Kim, Ho Young; Lee, Ji Youn; Hsieh, Chia-Ju; Taylor, Michelle; Luedtke, Robert R.; Mach, Robert H.Previous studies have confirmed that the binding of D(3) receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D(3) receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D(3) receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D(3) receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D(3) receptor affinities (Ki = 0.8-13.2 nM) with subtype selectivity to the D(2) receptor ranging from 22- to 180-fold. The beta-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC(50) = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D(3) receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT(3) receptors and TSPO. The results of this study revealed that a new class of selective D(3) receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.Item Design and Synthesis of D(3)R Bitopic Ligands with Flexible Secondary Binding Fragments: Radioligand Binding and Computational Chemistry Studies(MDPI, 2024-01-11) Tian, Gui-Long; Hsieh, Chia-Ju; Taylor, Michelle; Lee, Ji Youn; Luedtke, Robert R.; Mach, Robert H.A 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.