Research activities have been devoted primarily to the application of principles of small molecular chemistry to problems in biology, with emphasis on the molecular mechanisms of drug metabolism and pharmacological processes, including neurotoxicity and neuroprotection.   

A major research interest concerns the molecular mechanisms of monoamine oxidase and cytochrome P-450 catalyzed oxidations and the identification of metabolic pathways that may contribute to the biological properties of the substrate molecules.   

Research Topics    

Current research topics include:   

(1) Synthesis of test compounds with respect to neurotoxicity and neuroprotection, including potential nitric oxide synthase inhibitors and evaluation of these and other test substances as dopaminergic neurotoxins or evaluation as potential neuroprotectants.   

(2) Enzyme mechanisms of catalysis. Chemical model studies have been developed and continue to be used to evaluate the mechanism of MAO catalysis (single electron transfer and/or hydrogen atom abstraction). Ongoing are syntheses of deuterium labeled compounds to study enzyme mechanisms and the use of tissue homogenate incubations to study metabolite formation and identification. In general: Techniques used include HPLC, NMR, Mass spectrometry (including GCMS and LCMS) syntheses of small molecules, enzyme studies and neurotoxic/neuroprotective models.   

(3) Evaluation of (S)-nicotine, N-methylanatabine and other extracts from tobacco. Smokers in general have a lower incidence of Parkinson's Disease and it has been recently reported that the brains of smokers have lower levels of monoamine oxidase (MAO) A and B. This raises a question regarding the possibility that this inhibition of MAO may be neuroprotective. We are, therefore, evaluating compounds and extracts for their MAO inhibitory properties, in vitro, and are using a known measure of neurotoxicity which is the depletion of striatal levels of dopamine in animal models, to further characterize the potential neuroprotective properties of these compounds.   

(4) Characterization of species differences with respect to MAO. We are evaluating a panel of compounds with respect to their substrate and inhibitor properties for MAO-A and MAO-B. We are evaluating a variety of tissues in 8 species including the human, sub-human primates and rodents. A knowledge of these species differences can lead to better animal models for development of neuroprotective agents.    

Selected Representative Publications:    

Van der Schyf, C. J., Castagnoli, K., Usuki, E., Fouda, H. G., Rimoldi, J. M., and Castagnoli, Jr., N. (1994) Metabolic Studies on Haloperidol and its Tetrahydro-pyridine Analog in C57BL/6 Mice. Chem. Res. Toxicol., 7, 281-285.   

Flaherty, P., Castagnoli, K., Wang, Y.-X., and Castagnoli, Jr., N. (1996) Synthesis and Selective MAO-B Inhibiting properties of 1-Methyl-4-(1,2,3,6-Tetrahydro-pyridyl) Carbamate Derivatives, Potential Prodrugs of (R)- and (S)-Nordeprenyl. J. Med. Chem., 39, 4756-4761.   

Castagnoli, K., Palmer, S., Anderson, A., Bueters, T., Castagnoli, Jr., N. (1997) The Neuronal Nitric Oxide Synthase Inhibitor 7-Nitroindazole Also Inhibits the Monoamine Oxidase-B-catalyzed Oxidation of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Chem. Res. Toxicol.,10, 364-368.   

Franot, C., Mabic, S., and Castagnoli, N., Jr. (1998) Chemical Model Studies on the Monoamine Oxidase-B Catalyzed Oxidation of 4-Substituted 1-Cyclopropyl-1,2,3,6-tetrahydropyridines. Bioorg. & Med. Chem., 6, 283-291.   

Castagnoli, Jr., N., Liu, X., Shigenanga, M., Wardrop, R., and Castagnoli, K. (1998) The Metabolic Fate of (S)-Nicotine and Its Pyrrolic Analog b-Nicotyrine. In Nicotine Safety and Toxicity, Chapter 6. Ed. Benowitz, N. L., Oxford Univ. Press, New York, NY, pp. 57-65.   

Zhao, Z., Mabic, S., Franot, C., Castagnoli, K., and Castagnoli, Jr., N. (In press, 1998) Rat Liver Microsomal Enzyme Catalyzed Oxidation of 1-Cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine. Bioorg. & Med. Chem.   

Liu, X., Zang, L., Igarashi, K., Castagnoli, K., Van der Schyf, C. J. and N. Castagnoli, Jr. (in preparation, 1998) In Vitro Biotransformation of the Tobacco Alkaloid 1-Methyl-2-(3-pyridyl)pyrrole (b -Nicotiine).   

Castagnoli, N., Jr., Castagnoli, K., Van der Schyf, C, and Liu, X. (in preparation, 1998) In Vivo Biotransformation of b-Nicotine, a Minor Tobacco Alkaloid. 

Castagnoli, N., Jr., Petzer, J., Steyn, Salome, Castagnoli, K., Chen, J-F., Schwarzschild, M and Van der Schyf, C. (2003) Monoamine oxidase B inhibition and neuroprotection: Studies on selective adenosine A2A receptor antagonists. Neurology, 61 (Supplement 6), S62-S68.

Bibbiani, F., Oh, J., Petzer, J., Castagnoli, Jr., N., Chen, J-F., Schwarzchild, M. and Chase, T. (2003) A2A antagonist prevents dopamine agonist-induced motor complications in animal models of PD. Exp. Neuro., 184, 285-294.

Beeler, A., Gadepalli, R., Steyn, Salome, Castagnoli, Jr., N. and Rimoldi, J. (2003) Synthesis and in-vitro biological evaluation of fluoro-substituted-4-phenyl-1,2,3,6-tetrahydropyridines as monoamine oxidase B substrates. Bioorg. Med. Chem., 11, 5229-5234.

Bissel, P. and Castagnoli, Jr. , N.(2005) Studies on the cytochrome P450 catalyzed oxidation of 13C labeled 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine by 13C NMR. Bioorg. Med. Chem., 13, 2975-2980.

Frederick, R., Ooms, F., Castagnoli, Jr., N., Petzer, J., Feng, J-F, Schwarzschild, M., Van der Schyf, C., and Wouter, J. (2005) (E)-8-(3-Chlorostyryl)-1,3,7-trimethylxanthine, a caffeine derivative acting both as antagonist of adenosine A2A receptors and as inhibitor of MAO-B. Acta Cryst., C61, o531-o532.