Irreversible ligands targeting the dopamine D2 receptor

The dopamine D2 receptor (D2R) is a Family A G protein-coupled receptor (GPCR) and therapeutic target for Parkinson’s disease and schizophrenia. Irreversible inhibitors inherently form covalent bonds with chemical substrates and have therefore been extensively utilized for structural studies of proteins to elucidate potential binding domains. We aim to synthesize a series of irreversible derivatives of the bitopicligand SB269652 (the first identified drug-like negative allosteric modulator of the dopamine D2 receptor) as pharmacological tools to probe the structural basis of D2R orthosteric and allosteric binding pockets, and corresponding modulation and signalling mechanisms. These compounds will utilize established functional group protocols for such studies including a photoactivatable aryl azide group for photolabeling and an aryl isothiocyanate for direct conjugation to the protein.

The synthetic approach that will be used to prepare these irreversible derivatives of SB269652 is exemplified in scheme 1, whereby the key primary aromatic amine of the SB269652 derivative can be converted to the bioconjugatable isothiocyanate (red) or the photoactivatable azide (blue). We envision irreversible ligands of this nature as extremely valuable tools for ‘locking’ the dopamine D2 receptor into a specific conformation, which may allow the crystallization of this elusive receptor and thereby produce invaluable structural information to enhance drug discovery programs to address the aforementioned disease states.