An investigation of the in vitro reversibility of MAO inhibition by lazabemide
4.4. Discussion and conclusion
As mentioned, lazabemide and related N-(2-aminoethyl)carboxamides are mechanism-based inhibitors of MAO-B. While inhibition is irreversible in vitro, in vivo, enzyme activity returns to baseline values by 36 h after drug discontinuation (Dingemanse et al., 1997; Fowler et al., 1993). Since enzyme recovery may require as much as 40 days following inhibition with irreversible inhibitors, this demonstrates that lazabemide inhibition in vivo is essentially reversible (Fowler et al., 2005; Fowler et al., 2015). Due to its unique mechanism of action, lazabemide results in rapid and complete MAO-B inhibition, which highlights its potential efficacy in the in vivo setting. A further point of interest is that lazabemide is a highly specific inhibitor of MAO-B over the MAO-A isoform. Considering its reversibility of in vivo inhibition, potential high efficacy and complete MAO-B inhibition, and high specificity, lazabemide may be considered an ideal MAO-B inhibitor for the treatment of neurodegenerative disorders such as Alzheimer’s disease and PD. This compound will be expected to possess a very low risk of causing adverse effects such as the potentiation of tyramine-induced hypertension, which is associated with MAO-A inhibition, particularly irreversible MAO-A inhibition (Da Prada et al., 1988; Flockhart, 2012). Although the development of lazabemide has been discontinued, related compounds in this class may still be considered for future development as MAO-B specific inhibitors. Furthermore, lazabemide may still be useful for experimental work and a
clear understanding of its mechanism of action is therefore required. By characterising the in vitro interaction of lazabemide with human MAO-B, the present study contributes to knowledge in this respect.
Acknowledgements
This work is based on the research supported in part by the Medical Research Council and National Research Foundation of South Africa (Grant specific unique reference numbers (UID) 85642, 96180). The Grantholders acknowledge that opinions, findings and conclusions or recommendations expressed in any publication generated by the NRF supported research are that of the authors, and that the NRF accepts no liability whatsoever in this regard.
Conflict of interest
The authors declare no conflicts of interest in this work.
References
1. Berlin, I., Aubin, H.J., Pedarriosse, A.M., Rames, A., Lancrenon, S. & Lagrue, G.
2002. Lazabemide in Smoking Cessation Study Investigators. Lazabemide, a selective, reversible monoamine oxidase B inhibitor, as an aid to smoking cessation.
Addiction, 97(10):1347-1354.
2. Binda, C., Li, M., Hubalek, F., Restelli, N., Edmondson, D.E. & Mattevi, A. 2003.
Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures. Proceedings of the national academy of science of the United States of America, 100(17):9750-9755.
3. Cesura, A.M., Borroni, E., Gottowik, J., Kuhn, C., Malherbe, P., Martin, J. & Richards, J.G. 1999. Lazabemide for the treatment of Alzheimer's disease: rationale and therapeutic perspectives. Advances in neurology, 80:521-528.
4. Cesura, A.M., Galva, M.D., Imhof, R., Kyburz, E., Picotti, G.B. & Da Prada, M. 1989.
[3H]Ro 19-6327: a reversible ligand and affinity labelling probe for monoamine oxidase-B. European journal of pharmacology, 162(3):457-465.
5. Cesura, A.M., Imhof, R., Takacs, B., Galva, M.D., Picotti, G.B. & Da Prada, M. 1988.
[3H]Ro 16-6491, a selective probe for affinity labelling of monoamine oxidase type B in human brain and platelet membranes. Journal of neurochemistry, 50(4):1037- 1043.
6. Cesura, A.M., Muggli-Maniglio, D., Lang, G., Imhof, R. & Da Prada, M. 1990.
Monoamine oxidase inhibition by moclobemide and 2-amino-ethyl carboxamide derivatives: mode of action and kinetic characteristics. Journal of neural
transmission, 32:165-170.
7. Da Prada, M., Zürcher, G., Wüthrich, I. & Haefely, W.E. 1988. On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. Journal of neural transmission, 26:31-56.
8. Dingemanse, J., Wood, N., Jorga, K. & Kettler, R. 1997. Pharmacokinetics and pharmacodynamics of single and multiple doses of the MAO-B inhibitor lazabemide in healthy subjects. British journal of clinical pharmacology, 43(1):41-47.
9. Edmondson, D.E., Binda, C., Wang, J., Upadhyay, A.K. & Mattevi, A. 2009.
Molecular and mechanistic properties of the membrane-bound mitochondrial monoamine oxidases. Biochemistry, 48(20):4220-4230.
10. Edmondson, D.E., Mattevi, A., Binda, C., Li, M. & Hubálek, F. 2004. Structure and mechanism of monoamine oxidase. Current medicinal chemistry, 11(15):1983-93.
11. Edmondson, D.E. 2014. Hydrogen peroxide produced by mitochondrial monoamine oxidase catalysis: biological implications. Current pharmaceutical design, 20(2):155- 160.
12. Flockhart, D.A. 2012. Dietary restrictions and drug interactions with monoamine oxidase inhibitors: an update. Journal of clinical Psychiatry, 73(1):17-24.
13. Fowler, J.S., Logan, J., Shumay, E., Alia-Klein, N., Wang, G.J. & Volkow, N.D. 2015.
Monoamine oxidase: radiotracer chemistry and human studies. Journal of labelled compounds and radiopharmaceuticals, 58(3):51-64.
14. Fowler, J.S., Logan, J., Volkow, N.D. & Wang, G.J. 2005. Translational neuroimaging: positron emission tomography studies of monoamine oxidase.
Molecular imaging and Biology, 7(6):377-387.
15. Fowler, J.S., Volkow, N.D., Logan, J., Schlyer, D.J., MacGregor, R.R., Wang, G.J., Wolf, A.P., Pappas, N., Alexoff, D. & Shea, C. 1993. Monoamine oxidase B (MAO B) inhibitor therapy in PD: the degree and reversibility of human brain MAO B inhibition by Ro 19 6327. Neurology, 43(10):1984-1992.
16. Fowler, J.S., Volkow, N.D., Wang, G.J., Logan, J., Pappas, N., Shea, C. &
MacGregor, R. 1997. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobioogical Aging, 18(4):431-435.
17. Lum, C.T. & Stahl, S.M. 2012. Opportunities for reversible inhibitors of monoamine oxidase-A (RIMAs) in the treatment of depression. CNS Spectrums, 17(3):107-120.
18. Maurel, A., Hernandez, C., Kunduzova, O., Bompart, G., Cambon, C., Parini, A. &
Francés, B. 2003. Age-dependent increase in hydrogen peroxide production by cardiac monoamine oxidase A in rats. The American journal of physiology - Heart circulatory physiology, 284(4):1460-1467.
19. Meiring, L., Petzer, J.P. & Petzer, A. 2017. C6- and C7-Substituted 3,4-dihydro- 2(1H)-quinolinones as inhibitors of monoamine oxidase. Drug Research (Stuttg), 67(3):170-178.
20. Müller, T. 2016. Emerging approaches in PD - adjunctive role of safinamide.
Therapeutics and clinical risk management, 12:1151-1160.
21. Petzer, A., Harvey, B.H., Wegener, G. & Petzer, J.P. 2012. Azure B, a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase.
Toxicology and applied pharmacology, 258(3):403-409.
22. Petzer, A., Pienaar, A. & Petzer, J.P. 2013. The inhibition of monoamine oxidase by esomeprazole. Drug Research (Stuttg), 63(9):462-467.
23. Ramsay, R.R. 2013. Inhibitor design for monoamine oxidases. Current pharmaceutical design, 19(14):2529-2539.
24. Ramsay, R.R. 2016. Molecular aspects of monoamine oxidase B. Progress in neuro-psychopharmacology and biological Psychiatry, 69:81-89.
25. Soriato, G., Focati, M.P., Brescello, R., Cotarca, L. & Giovanetti, R. 2008.
Pharmaceutical preparations of crystalline lazabemide. Patent WO/2008/010794.
26. Strydom, B., Bergh, J.J. & Petzer, J.P. 2012. The inhibition of monoamine oxidase by 8-(2-phenoxyethoxy)caffeine analogues. Arzneimittelforschung, 62(11):513-518.
27. Sturm, S., Forsberg, A., Nave, S., Stenkrona, P., Seneca, N., Varrone, A., Comley, R.A., Fazio, P., Jamois, C., Nakao, R., Ejduk, Z., Al-Tawil, N., Akenine, U., Halldin, C., Andreasen, N. & Ricci, B. 2016. Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer's disease and elderly controls after oral administration of sembragiline. European journal of nuclear medicine and molecular imaging, [Epub ahead of print].
28. Wu, J.B., Shao, C., Li, X., Li, Q., Hu, P., Shi, C., Li, Y., Chen, Y.T., Yin, F., Liao, C.P., Stiles, B.L., Zhau, H.E., Shih, J.C. & Chung, L.W. 2014. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. Journal of clinical investigation, 124(7):2891-2908.
29. Xu, S., Adisetiyo, H., Tamura, S., Grande, F., Garofalo, A., Roy-Burman, P. &
Neamati, N. 2015. Dual inhibition of survivin and MAOA synergistically impairs growth of PTEN-negative prostate cancer. British journal of Cancer, 113(2):242-251.
30. Youdim, M.B. & Bakhle, Y.S. 2006. Monoamine oxidase: isoforms and inhibitors in PD and depressive illness. British journal of pharmacology, 147(1):287-296.
31. Youdim, M.B., Edmondson, D. & Tipton, K.F. 2006. The therapeutic potential of monoamine oxidase inhibitors. Nature reviews neuroscience, 7(4):295-309.
Supplementary material
Figure S4.1. 1H NMR, 13C NMR and DEPT-135 spectra for lazabemide