Browsing by Subject "Receptors, Dopamine D3 / metabolism"
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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 Interaction of Ligands for PET with the Dopamine D3 Receptor: In Silico and In Vitro Methods(MDPI, 2021-04-02) Hsieh, Chia-JI; Riad, Aladdin; Lee, Ji Youn; Sahlholm, Kristoffer; Xu, Kuiying; Luedtke, Robert R.; Mach, Robert H.[(18)F]Fallypride and [(18)F]Fluortriopride (FTP) are two different PET radiotracers that bind with sub-nanomolar affinity to the dopamine D3 receptor (D3R). In spite of their similar D3 affinities, the two PET ligands display very different properties for labeling the D3R in vivo: [(18)F]Fallypride is capable of binding to D3R under "baseline" conditions, whereas [(18)F]FTP requires the depletion of synaptic dopamine in order to image the receptor in vivo. These data suggest that [(18)F]Fallypride is able to compete with synaptic dopamine for binding to the D3R, whereas [(18)F]FTP is not. The goal of this study was to conduct a series of docking and molecular dynamic simulation studies to identify differences in the ability of each molecule to interact with the D3R that could explain these differences with respect to competition with synaptic dopamine. Competition studies measuring the ability of each ligand to compete with dopamine in the beta-arrestin assay were also conducted. The results of the in silico studies indicate that FTP has a weaker interaction with the orthosteric binding site of the D3R versus that of Fallypride. The results of the in silico studies were also consistent with the IC50 values of each compound in the dopamine beta-arrestin competition assays. The results of this study indicate that in silico methods may be able to predict the ability of a small molecule to compete with synaptic dopamine for binding to the D3R.