Bioorganic & medicinal chemistry, 2017-10, Vol.25 (19), p.5084-5094
2017
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Potent haloperidol derivatives covalently binding to the dopamine D2 receptor
- Ist Teil von
- Bioorganic & medicinal chemistry, 2017-10, Vol.25 (19), p.5084-5094
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- [Display omitted] The dopamine D2 receptor (D2R) is a common drug target for the treatment of a variety of neurological disorders including schizophrenia. Structure based design of subtype selective D2R antagonists requires high resolution crystal structures of the receptor and pharmacological tools promoting a better understanding of the protein-ligand interactions. Recently, we reported the development of a chemically activated dopamine derivative (FAUC150) designed to covalently bind the L94C mutant of the dopamine D2 receptor. Using FAUC150 as a template, we elaborated the design and synthesis of irreversible analogs of the potent antipsychotic drug haloperidol forming covalent D2R-ligand complexes. The disulfide- and Michael acceptor-functionalized compounds showed significant receptor affinity and an irreversible binding profile in radioligand depletion experiments.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0968-0896eISSN: 1464-3391DOI: 10.1016/j.bmc.2017.06.034Titel-ID: cdi_proquest_miscellaneous_1915347535
- Format
- –
- Schlagworte
- Antipsychotic Agents - chemistry, Antipsychotic Agents - pharmacology, Chemical probe, Covalent ligand, Disulfide tethering, Dopamine D2 receptor, Dopamine D2 Receptor Antagonists - chemistry, Dopamine D2 Receptor Antagonists - pharmacology, G protein-coupled receptor, Haloperidol, Haloperidol - analogs & derivatives, Haloperidol - pharmacology, Humans, Ligands, Molecular Docking Simulation, Point Mutation, Protein Binding, Radioligand Assay, Receptors, Dopamine D2 - chemistry, Receptors, Dopamine D2 - genetics, Receptors, Dopamine D2 - metabolism, Schizophrenia - drug therapy