mi-Opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation

Abstract

Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for m-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28–42 % overall yields. The approach has a con­siderable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antino­cic­eptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid–dopamine receptor heterobivalent ligands.