1,1′-Disubstituted Ferrocenes as Molecular Hinges in Mono- and Bivalent Dopamine Receptor Ligands

Abstract

On the basis of previous work on dopaminergic partial agonists of type 1 and 2, disubstituted ferrocenes are presented as valuable arene bioisosteres. Because substituents at the distal cyclopentadienyl ring are able to adjust the relative disposition that is required for ligand binding, disubstituted ferrocenes can act as molecular hinges. Taking advantage of click chemistry, the regioselective construction and functionalization of the target molecules is reported. Thus triazole derived appendages were used for the fine-tuning of biological activity and for the attachment of linker units generating bivalent GPCR ligands. Receptor binding was evaluated by radioligand displacement experiments, revealing superaffinity with sub- to single-digit nanomolar K(i) values for particular test compounds. As a neutral antagonist at the dopamine receptors D3 and D4 and a potent partial agonist at the D2 subtype (intrinsic activity = 57%, EC(50) = 2.5 nM), the bifunctional ferrocene 10b revealed a novel and unique activity profile.