Conformational distribution of the potentially neurotoxic metabolite of haloperidol, HPP⁺, by NMR spectroscopy, X-ray crystallography and molecular dynamics simulations

In order to gain more insight into the mechanisms underlying mitochondrial inhibition by haloperidol (HP) pyridinium metabolites, we have studied the three dimensional structure of these compounds. In this paper we report the results of experimental (NMR studies in solution, X-ray diffraction) and theoretical methods (molecular dynamics) applied to HPP⁺. The chlorophenyl and pyridinium rings are found not to be strictly coplanar and a high degree of mobility was observed in the butyroxy chain. Calculations have shown that the most stable structures adopt conformations corresponding to either gauche or trans rotamers. From these data, a model for the interaction of HPP⁺ with electron transfer complexes in the mitochondrial respiratory chain has been proposed.