- Design of a True Bivalent Ligand with Picomolar Binding Affinity for a G Protein-Coupled Receptor Homodimer
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Bivalent ligands have emerged as chemical tools to study G protein-coupled receptor dimers. Using a combination of computational, chemical, and biochemical tools, here we describe the design of bivalent ligand 13 with high affinity (KDB1 = 21 pM) for the dopamine D2 receptor (D2R) homodimer. Bivalent ligand 13 enhances the binding affinity relative to monovalent compound 15 by 37-fold, indicating simultaneous binding at both protomers. Using synthetic peptides with amino acid sequences of transmembrane (TM) domains of D2R, we provide evidence that TM6 forms the interface of the homodimer. Notably, the disturber peptide TAT-TM6 decreased the binding of bivalent ligand 13 by 52-fold and had no effect on monovalent compound 15, confirming the D2R homodimer through TM6 ex vivo. In conclusion, by using a versatile multivalent chemical platform, we have developed a precise strategy to generate a true bivalent ligand that simultaneously targets both orthosteric sites of the D2R homodimer.
- Pulido, Daniel,Casadó-Anguera, Verònica,Pérez-Benito, Laura,Moreno, Estefanía,Cordomí, Arnau,López, Laura,Cortés, Antoni,Ferré, Sergi,Pardo, Leonardo,Casadó, Vicent,Royo, Miriam
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supporting information
p. 9335 - 9346
(2018/10/24)
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- Target-specific ligands and gadolinium-based complexes for imaging of dopamine receptors: Synthesis, binding affinity, and relaxivity
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Magnetic resonance imaging (MRI) and positron emission tomography (PET) are two extremely important imaging modalities with unlimited tissue penetration. Molecular imaging is a field by which specific targets or biological processes are imaged. MRI, which is used for functional imaging and for the diagnosis of a broad range of pathologic conditions, suffers from limited specificity and intrinsically low sensitivity. One possibility to alleviate partially these limitations is to use contrast agents (CAs) and more importantly target-specific CAs. We have developed a modular synthesis of novel ligands and gadolinium(III)-based target-specific MRI CAs with high relaxivity and high binding affinity toward the dopamine receptors. The prepared ligands and MRI CAs are based on spiperone as targeting moiety. The prepared target-specific CAs can potentially be used for in vitro and possibly in vivo MR imaging of dopaminergic receptors. Importantly the ligands prepared using the modular approach presented in this paper may also be useful for other imaging modalities such as PET (or SPECT) by just replacing, at the last stage of the synthesis, the gadolinium cation by other metal cations having relatively long half-lives, such as 64Cu, 89Zr, 11In, and more.
- Zigelboim, Isaac,Weissberg, Avi,Cohen, Yoram
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p. 7001 - 7012
(2013/08/23)
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- Practical synthesis of p-aminophenethylspiperone (NAPS), a high-affinity, selective D2-dopamine receptor antagonist
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Because attempts to scale up the published synthetic preparation of p-aminophenethylspiperone (NAPS) by N-alkylation of spiperone with 4-nitrophenethyl bromide followed by reduction gave poor yields and difficulties during purification, an alternative synthetic approach has been developed. Use of 4-(N-tert-butyloxycarbonyl) aminophenethyl bromide to alkylate spiperone followed by the Boc group deprotection gave NAPS in 56% yield. This procedure provides an improved and efficient synthesis of the important high-affinity, selective D2-dopamine receptor antagonist NAPS. Copyright Taylor & Francis Group, LLC.
- Jin, Chunyang,Mayer, Louise D.,Lewin, Anita H.,Rehder, Kenneth S.,Brine, George A.
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p. 816 - 823
(2008/09/16)
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- Rapid and efficient synthesis of high-purity fluorine-18 labeled haloperidol and spiperone via the nitro precursor in combination with a new HPLC separation method
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We have completed a convenient synthesis of fluorine-18 labeled butyrophenone neuroleptics from their nitro precursors. Thus, we have developed an efficient single-columm HPLC system using a C18-bonded vinyl alcohol copolymer gel (octadecyl polymer, ODP) column and strongly alkaline solvent systems for purifying of the 18F-labeled butyrophenone neuroleptics obtained by a single-stp 18F-for-nitro exchange reaction. The method has been applied to the synthesis of two typical butyrophenone neuroleptics ([18F]haloperidol and [18F]spiperone) with high purity in high yield. With information concerning the optimized conditions for the 18F-for-nitro exchange reaction, the synthetic method would be useful for synthesizing various 18F-labeled compounds.
- Hashizume, Kazunari,Hashimoto, Naoto,Miyake, Yoshihiro
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p. 681 - 687
(2007/10/03)
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