Conformational distribution of the potentially neurotoxic metabolite of haloperidol, HPP+, by NMR spectroscopy, X-ray crystallography and molecular dynamics simulations
[en] 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.
Disciplines :
Chemistry
Author, co-author :
Ooms, Frédéric ; Université de Liège - ULiège > HEC Liège Research > HEC Liège Research: Strategy & Performance for the Society ; Lab. de Chim. Molec. Structurale, Fac. Univ. Notre-Dame de la Paix, Namur, Belgium
Wouters, Johan; Lab. de Chim. Molec. Structurale, Fac. Univ. Notre-Dame de la Paix, Namur, Belgium
Durant, Francois; Lab. de Chim. Molec. Structurale, Fac. Univ. Notre-Dame de la Paix, Namur, Belgium
Castagnoli Jr., Neal; Department of Chemistry, Harvey W. Peters Center, Virginia Polytech. Inst. State Univ., Blacksburg, VA 24061, United States
Van't Land, Clinton; Department of Chemistry, Harvey W. Peters Center, Virginia Polytech. Inst. State Univ., Blacksburg, VA 24061, United States
Dockendolf, Gisella; Dept. of Pharmaceutical Chemistry, Potchefstroom Univ. Chrstn. H., Potchefstroom 2520, South Africa
Glass, Thomas; Department of Chemistry, Harvey W. Peters Center, Virginia Polytech. Inst. State Univ., Blacksburg, VA 24061, United States
Van Der Schyf, Cornelis J.; Department of Chemistry, Harvey W. Peters Center, Virginia Polytech. Inst. State Univ., Blacksburg, VA 24061, United States ; Dept. of Pharmaceutical Chemistry, Potchefstroom Univ. Chrstn. H., Potchefstroom 2520, South Africa ; Dept. Biomed. Sci. and Pathobiology, VA-MD Regl. Coll. of Vet. Medicine, Virginia Polytech. Inst. State Univ., Blacksburg, VA 24061, United States
Language :
English
Title :
Conformational distribution of the potentially neurotoxic metabolite of haloperidol, HPP+, by NMR spectroscopy, X-ray crystallography and molecular dynamics simulations
Publication date :
1997
Journal title :
Journal of the Chemical Society. Perkin Transactions 2
R. L. DesJarlais, G. L. Seibel, I. D. Kuntz, P. S. Furth, J. C. Alvarez, P. R. Ortiz de Montellano, D. L. DeCamp, L. M. Babe and C. S. Craik, Proc. Natl. Acad. Sci. USA, 1990, 87, 6644.
E. Rutenber, E. B. Fauman, R. J. Keenan, S. Fong, P. S. Furth, P. R. Ortiz de Montellano, E. Meng, I. D. Kuntz, D. L. DeCamp and R. Salto, J. Biol. Chem., 1993, 268, 15 343.
C. M. Oshiro, I. D. Kuntz and J. S. Dixon, J. Comput.-Aided Mol. Des., 1995, 9, 113.
J. M. Kane, M. Woerner and J. Lieberman, in Dyskinesia Research and Treatment, ed. D. E. Casey, T. Chase, A. V. Christensen and J. Gerlach, Springer, Berlin, 1985, pp. 72-78.
E. Christensen, J. E. Moller and A. Faurbye, Acta Psychiatr. Scand., 1970, 46, 14.
F. M. Benes, P. A. Paskewich and V. B. Domesick, Science, 1983, 221, 969.
F. M. Benes, P. A. Paskewich, J. Davidson and V. B. Domesick, Brain Res., 1985, 329, 265.
R. Dom, Acta Neurol. Pychiatr. Belg., 1967, 67, 755.
S. P. Mahadik, H. Laev, A. Korenovsk and S. E. Karpiak, Biol. Psychiatry, 1988, 24, 199.
C. K. Meshul and D. E. Casey, Brain Res., 1989, 489, 338.
C. K. Meshul and S. E. Tan, Synapse, 1994, 18, 205.
C. K. Meshul, J. F. Buckman, C. Allen, J. P. Riggan and D. J. Feller, Synapse, 1996, 22, 350.
C. K. Meshul and S. E. Tan, Synapse, 1994, 18, 205.
R. C. Roberts, L. A. Gaither, X-M. Gao, S. M. Kashyap and C. A. Tamminga, Synapse, 1995, 20, 234.
B. Subramanyam, H. Rollema, T. Woolf and N, Castagnoli, Jr., Biochem. Biophys. Res. Commun., 1990, 166, 238.
B. Subramanyam, T. Woolf and N. Castagnoli, Jr., Chem. Res. Toxicol., 1991, 4, 123.
C. J. Van der Schyf, K. Castagnoli, E. Usuki, H. G. Fouda, J. M. Rimoldi and N. Castagnoli, Jr., Chem. Res. Toxicol., 1994, 7, 281.
B. Subramanyam, S. M. Pond, D. W. Eyles, H. A. Whiteford, H. G. Fouda and N. Castagnoli, Jr., Biochem. Biophy. Res. Commun., 1991, 181, 573.
D. W. Eyles, H. R. McLennan, A. Jones, J. J. McGrath, T. J. Stedman and S. M. Pond, Clin. Pharmacol. Ther., 1994, 56, 512.
K. M. Avent, E. Usuki, D. W. Eyles, R. Keeve, C. J. Van der Schyf, N. Castagnoli, Jr. and S. M. Pond, Life Sci., 1996, 59, 1473.
H. Rollema, M. Skolnik, J. D'Engelbronner, K. Igarashi, E. Usuki and N. Castagnoli, Jr., J. Pharmacol. Exp. Ther., 1994, 268, 380.
J. Bloomquist, E. King, A. Wright, C. Mytilineou, K. Kimura, K. Castagnoli and N. Castagnoli, Jr., J. Pharmacol. Exp. Ther., 1994, 270, 822.
L. J. Mienie, J. J. Bergh, E. Van Staden, S. J. Steyn, S. M. Pond, N. Castagnoli, Jr. and C. J. Van der Schyf, Life Sci., 1997, 61, 265.
W. J. Nicklas, M. S. Saporito, A. Basma, H. M. Geller and R. E. Heikkila, Ann. N. Y. Acad. Sci., 1992, 648, 28.
M. S. Saporito, R. E. Heikkila, S. K. Youngster, W. J. Nicklas and H. M. Geller, J. Pharmacol. Exp. Ther., 1992, 260, 1400.
M. R. Gluck, S. K. Youngster, R. R. Ramsay, T. P. Singer and W. J. Nicklas, J. Neurochem., 1994, 63, 655.
R. R. Ramsay, J. I. Salach and T. P. Singer, Biochem. Biophys. Res. Commun., 1986, 134, 743.
R. R. Ramsay, J. I. Salach, J. Dadgar and T. P. Singer, Biochem. Biophys. Res. Commun., 1993, 135, 285.
M. R. Gluck, S. K. Youngster, R. R. Ramsay, T. P. Singer and W. J. Nicklas, J. Neurochem., 1994, 63, 655.
Q. Gao and W. L. Parker, Tetrahedron, 1996, 52, 2291.
L. F. Newcomb, T. S. Haque and S. H. Gellman, J. Am. Chem. Soc., 1995, 117, 6509.
F. H. Allen, O. Kennard and R. Taylor, Acc. Chem. Res., 1983, 16, 146.
C. P. Brock and R. P. Minton, J. Am. Chem. Soc., 1989, 111, 4586.
A. Almenningen, O. Bastiansen, L. Fernholt, B. N. Cyvin, S. J. Cyvin and S. Samdal, J. Mol. Struct. 1985, 128, 59.
W. Klyne and V. Prelog, Experientia, 1960, 16, 521
InsightII User Guide 1995, Biosym/Molecular Simulations Inc. San Diego, CA.
G. B. McGaughey, E. L. Stewart and J. P. J. Bowen, J. Comput. Chem., 1996, 17, 1395.
C. Altomare, P.-A. Carrupt. N. El Tayar and B. Testa, Helv. Chim. Acta, 1991, 74, 290.
J. Wouters, G. Evrard, F. Durant, A. Kalgutkar and N. Castagnoli, Jr., Acta Crystallogr, Sect. C., 1996, 52, 1033.
K. McNaught, U. Thull, P. A. Carrupt, C. Altomare, S. Cellamare, A. Carotti, B. Testa, P. Jenner and D. Marsden, Biochem. Pharmacol., 1996, 51, 1503.
H. Rollema, M. Skolnik, J. D'Engelbronner, K. Igarashi, E. Usuki and N. Castagnoli, Jr., J. Pharmacol. Exp. Ther., 1994, 268, 380.
G. Baudoux and G. Evrard, NONIUS93. Program for Data Reduction, 1993.
G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46, 467.
G. M. Sheldrick, SHELXL93. Program for the Refinement of Crystal Structures, University of Göttingen, Federal Republic of Germany, 1993.
J. R. Maple, U. Dinur and A. T. Hagler, Proc. Natl. Sci. USA, 1985, 85, 5350.
J. R. Maple, M.-J. Hwang, T. P. Stockfisch, U. Dinur, M. Waldman, C. S. Ewig and A. T. Hagler, J. Comput. Chem., 1994, 15, 162.
