Browsing by Author "Kim, Ho Young"
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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 In vitro characterization of [(125)I]HY-3-24, a selective ligand for the dopamine D3 receptor(Frontiers Media S.A., 2024-04-24) Lee, Ji Youn; Kim, Ho Young; Martorano, Paul; Riad, Aladdin; Taylor, Michelle; Luedtke, Robert R.; Mach, Robert H.INTRODUCTION: Dopamine D3 receptor (D3R) ligands have been studied for the possible treatment of neurological and neuropsychiatric disorders. However, selective D3R radioligands for in vitro binding studies have been challenging to identify due to the high structural similarity between the D2R and D3R. In a prior study, we reported a new conformationally-flexible benzamide scaffold having a high affinity for D3R and excellent selectivity vs. D2R. In the current study, we characterized the in vitro binding properties of a new radioiodinated ligand, [(125)I]HY-3-24. METHODS: In vitro binding studies were conducted in cell lines expressing D3 receptors, rat striatal homogenates, and rat and non-human primate (NHP) brain tissues to measure regional brain distribution of this radioligand. RESULTS: HY-3-24 showed high potency at D3R (K(i) = 0.67 +/- 0.11 nM, IC(50) = 1.5 +/- 0.58 nM) compared to other D2-like dopamine receptor subtypes (D2R K(i) = 86.7 +/- 11.9 nM and D4R K(i) > 1,000). The K(d) (0.34 +/- 0.22 nM) and B(max) (38.91 +/- 2.39 fmol/mg) values of [(125)I]HY-3-24 were determined. In vitro binding studies in rat striatal homogenates using selective D2R and D3R antagonists confirmed the D3R selectivity of [(125)I]HY-3-24. Autoradiography results demonstrated that [(125)I]HY-3-24 specifically binds to D3Rs in the nucleus accumbens, islands of Calleja, and caudate putamen in rat and NHP brain sections. CONCLUSION: These results suggest that [(125)I]HY-3-24 appears to be a novel radioligand that exhibits high affinity binding at D3R, with low binding to other D2-like dopamine receptors. It is anticipated that [(125)I]HY-3-24 can be used as the specific D3R radioligand.