Synthesis and binding profile of haloperidol-based bivalent ligands targeting dopamine D2-like receptors |
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| Institution: | 1. Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suez Canal University, 41522 Ismailia, Egypt;1. Kazan State Architect and Civil Engineering University, Zelenaya, 1, 420043 Kazan, Russia;2. AE Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Science, Arbuzov Str., 8, 420088 Kazan, Russia;3. Laboratorie de Chimie de Coordination, CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France;1. Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China;2. Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China;3. Interdisciplinary Stem Cell Institute (ISCI), University of Miami Miller School of Medicine, Miami, Florida 33136;4. Department of Cardiology, Gulhane Military Medical Academy, Haydarpasa Hospital, 34668 Istanbul, Turkey;5. Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287;6. Departamento de Ciencias Basicas Biomedicas, Facultad de Ciencias de la Salud, Universidad de Talca, 3460000 Talca, Chile |
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| Abstract: | Homodimers of dopamine D2-like receptors are suggested to be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsychotics. This study describes the development of a series of novel bivalent molecules with a pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investigated in comparison to their monomeric analogues for their D2long, D2short, D3, and D4 receptor binding and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites. |
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| Keywords: | Bivalent ligands Dopamine Binding affinity GPCR dimers |
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