Potent haloperidol derivatives covalently binding to the dopamine D2 receptor

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.