Design,synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands |
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| Affiliation: | 1. INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre les Nancy, France;2. Groupe Hospitalier Pitié Salpêtrière, Université Pierre et Marie Curie, Paris, France;3. Hospital Italiano de Buenos Aires, Buenos Aires, Argentina;4. Mercy Medical Center, Baltimore, MD, USA;5. Hospital Provincial del Centenario, University of Rosario School of Medicine, Rosario, Argentina;6. The Research Institute, Springfield, MA, USA;7. Université Paris Descartes, INSERM U-1016, APHP, Hôpital Cochin, Paris, France;8. Universidad del Salvador Hospital de Gastroenterología Bonorino Udaondo, Buenos Aires, Argentina;9. Gastro One, Germantown, TN, USA;10. Bristol-Myers Squibb, Princeton, NJ, USA;11. Bristol-Myers Squibb, Wallingford, CT, USA;1. Laboratory of Medicinal Chemistry, CHU de Québec – Research Center (CHUL, T4), Québec, Qc, Canada;2. Department of Molecular Medicine, Faculty of Medicine, Laval University, Québec, Qc, Canada;1. Key Laboratory for Advanced Materials & Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Rd, Shanghai 200237, PR China;2. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China;1. Department of Bioengineering, School of Engineering, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-8656, Japan;2. Japan Science and Technology Agency, CREST, Chiyoda, Tokyo 102-0075, Japan;3. Green Devices Research Center, School of Materials Science, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa 923-1292, Japan |
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| Abstract: | The dopamine D3 receptor (D3R) was proposed as a therapeutic target for drug development to treat drug abuse and addiction and neuropsychiatric disorders. Several D3R-selective modulators over the dopamine D2 receptor (D2R) can avoid extrapyramidal symptoms (EPS) and hyperprolactinemia. However, few biased D3R ligands were identified or showed a narrow range of selectivity at the D3R over D2R because of their high sequence homology. Herein, we designed, synthesized and evaluated the binding affinity of a series of bitopic ligands: arypiperazine-phenyl-1,2,4-oxadiazoles. Compound 9e·HCl was the most potent and selective D3R modulator among these bitopic ligands. Molecular modeling revealed that D3R selectivity depends on the divergence of secondary binding pocket (SBP) in D3R and D2R. Specifically, non-conserved Tyr36, EL1 especially non-conserved Thr92 and Gly94, and EL2 Val180, Cys181 and Ser182 of D3R may contribute to D3R specificity over D2R. |
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| Keywords: | Dopamine D3 receptor Phenyl-1,2,4-oxadiazoles Structure–activity relationship Molecular modeling |
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