Empirical and molecular modeling study of the pyridinium species RHPP+, an abundant and potentially neurotoxic metabolite of haloperidol

Frédéric Ooms, Sébastien Delvosal, Johan Wouters, François Durant, Gisella Dockendolf, Clinton Van't Land, Thomas Glass, Neal Castagnoli, Cornelis J. Van Der Schyf

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The "reduced" haloperidol pyridinium metabolite (RHPP+) is found in the brain, plasma and urine of patients treated with the neuroleptic drug haloperidol (HP). RHPP+ is suspected to be neurotoxic through a mechanism that entails interference with the mitochondrial electron transport chain. We have studied the conformation of this flexible molecule in solution (using NMR) and in the solid state by single crystal X-ray analysis. Using the solid state structure as initial input, molecular dynamics runs indicated that the molecule preferably exists in an unfolded, rather than a folded conformation. We propose that the interaction of RHPP+ with complexes in the mitochondrial respiratory chain is stabilized primarily by an ionic bond involving the cationic nitrogen and secondarily by hydrogen-bond anchoring originating from the hydroxy group. A comparison with HPP+, the "unreduced" pyridinium metabolite of HP, suggests that this latter interaction may-among other considerations such as lipophilicity-account for differences in the in vitro toxicological profiles of RHPP+ and HPP+, which carries a ketone group in lieu of the hydroxy.

Original languageEnglish
Pages (from-to)1781-1787
Number of pages7
JournalJournal of the Chemical Society. Perkin Transactions 2
Issue number9
Publication statusPublished - 1 Sep 2000


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