Interactions of a boron-containing levodopa derivative on D2 dopamine receptor and its effects in a Parkinson disease model

Abstract

Levodopa is a cornerstone in Parkinson's disease treatment. Beneficial effects are mainly by binding on D₂ receptors. Docking simulations of a set of compounds including well-known D₂-ligands and a pool of Boron-Containing Compounds (BCC), particularly boroxazolidones with a tri/tetra-coordinated boron atom, were performed on the D₂ Dopamine receptor (D2DR). Theoretical results yielded higher affinity of the compound DPBX, a Dopaboroxazolidone, than levodopa on D2DR. Essential interactions with residues in the third and sixth transmembrane domains of the D2DR appear to be crucial to induce and stabilize interactions in the active receptor state. Results from a motor performance evaluation of a murine model of Parkinson's disease agree with theoretical results, as DPBX showed similar efficacy to that of levodopa for diminishing MPTP-induced parkinsonism. This beneficial effect was disrupted with prior Risperidone (D2DR antagonist) administration, supporting the role of D2DR in the biological effect of DPBX. In addition, DPBX limited neuronal loss in substantia nigra in a similar manner to that of levodopa administration.

Keywords: Boron; Boroxazolidone; Levodopa; MPTP; Parkinson.