Chiral Cyclic Aliphatic Linkers as Building Blocks for Selective Dopamine D₂ or D₃ Receptor Agonists

Linkers are emerging as a key component in regulating the pharmacology of bitopic ligands directed toward G-protein coupled receptors (GPCRs). In this study, the role of regio- and stereochemistry in cyclic aliphatic linkers tethering well-characterized primary and secondary pharmacophores targeting dopamine D₂ and D₃ receptor subtypes (D₂R and D₃R, respectively) is described. We introduce several potent and selective D₂R (rel-trans-16b; D₂R K_i = 4.58 nM) and D₃R (rel-cis-14a; D₃R K_i = 5.72 nM) agonists while modulating subtype selectivity in a stereospecific fashion, transferring D₂R selectivity toward D₃R via inversion of the stereochemistry around these cyclic aliphatic linkers [e.g., (-)-(1S,2R)-43 and (+)-(1R,2S)-42]. Pharmacological observations were supported with extensive molecular docking studies. Thus, not only is it an innovative approach to modulate the pharmacology of dopaminergic ligands described, but a new class of optically active cyclic linkers are also introduced, which can be used to expand the bitopic drug design approach toward other GPCRs.