Chiral Cyclic Aliphatic Linkers as Building Blocks for Selective Dopamine D or D 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 and D receptor subtypes (DR and DR, respectively) is described. We introduce several potent and selective DR (; DR = 4.58 nM) and DR (; DR = 5.72 nM) agonists while modulating subtype selectivity in a stereospecific fashion, transferring DR selectivity toward DR via inversion of the stereochemistry around these cyclic aliphatic linkers [e.g., and ]. 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.