The impact of secondary site interactions on the binding specificity of bitopic dopamine D2/D3 receptor ligands

Dysfunction of dopamine receptors and interruption of normal dopaminergic signaling have been linked to severe neuropsychiatric diseases such as schizophrenia, Parkinson's disease and depression. Although these receptors are among the most drug-targeted families of GPCRs, designing compounds with subtype-specific pharmacological profile remains challenging due to the structural similarities among the subtypes of the family. Considering the structural moieties of cariprazine, a prototypic drug with D3 receptor (D3R) preference, we report a library of bitopic analogues to explore how the orthosteric and secondary binding motifs, coupled with different linkers, affect D2R/D3R selectivity and activity. Compounds with promising dopamine receptor selectivities and binding affinities were further characterized on a GPCR panel and in functional assays. Our efforts resulted in an advanced lead compound (20b) with improved D3R and 5-HT2AR, as well as decreased D2R and 5-HT1AR potencies (EC50) compared to cariprazine. The cleaner receptor profile of this compound retained activities for the most important antidepressant mechanisms that were confirmed by reducing the depression-like behavior in mice.