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DOI: 10.1039/A705037B (Paper) Reference Section for: J. Chem. Soc., Perkin Trans. 2, 1997, 2627-2632

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

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Frederic Ooms, Johan Wouters, Francois Durant, Neal Castagnoli, Johan Wouters, Francois Durant, Neal Castagnoli, Jr., Clinton Vant Land, Gisella Dockendolf, Thomas Glass, Cornelis J. Van der Schyf , Clinton Vant Land, Gisella Dockendolf, Thomas Glass and Cornelis J. Van der Schyf

Abstract

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[hair space]+. 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[hair space]+ with electron transfer complexes in the mitochondrial respiratory chain has been proposed.

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