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 D 2 and D 3 receptor subtypes (D 2 R and D 3 R, respectively) is described. We introduce several potent and selective D 2 R ( rel - trans -16b; D 2 R K i = 4.58 nM) and D 3 R ( rel - cis -14a; D 3 R K i = 5.72 nM) agonists while modulating subtype selectivity in a stereospecific fashion, transferring D 2 R selectivity toward D 3 R via inversion of the stereochemistry around these cyclic aliphatic linkers [e.g., (−)-(1 S,2 R )-43 and (+)-(1 R,2 S )-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.