Summary
This study describes the serendipitous discovery of moclobemide, a short-acting MAO-A inhibitor which is in an advanced stage of clinical development as an antidepressant. The short duration of action of this MAO inhibitor containing a morpholine ring moiety is due to the complete reversibility (probably by metabolism of the inhibitory molecular species) of MAO-A inhibition. Since moclobemide is much more effective in vivo than expected from its in vitro activity, investigations to identify a possible metabolite(s) more active as MAO-A inhibitor than the parent compound were carried out. The study of the MAO inhibitory characteristics of several known and putative moclobemide metabolites did not allow the identification of a potent MAO-A inhibitor but led to the discovery of Ro 16-6491, a potent MAO-B inhibitor of novel chemical structure. Systematic chemical modification of the aromatic ring system of Ro 16-6491 finally provided Ro 19-6327 and Ro 41-1049 which are highly selective and reversible inhibitors of MAO-B and MAO-A, respectively. Tritiated derivatives of Ro 19-6327 and Ro 41-1049 were used in binding studies to elucidate their mechanisms of action and to study their cellular distribution by quantitative enzyme radioautography.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Arai R, Kimura H, Maedy T (1986) Topographic atlas of monoamine oxidase-containing neurons in the rat brain studied by an improved histochemical method. Neuroscience 19: 905–925.
Cesura AM, Imhof R, Takacs B, Galva MD, Picotti GB, 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. J Neurochem 50: 1037–1043.
Cesura AM, Galva MD, Imhof R, Kyburz E, Picotti GB, Da Prada M (1989) [3H]Ro 19-6327: a reversible ligand and affinity labelling probe for monoamine oxidase-B. Eur J Pharmacol 162: 457–465.
Da Prada M, Kettler R, Keller HH, Haefely WE (1983) Neurochemical effects in vitro and in vivo of the antidepressant Ro 11-1163, a specific and short-acting MAO-A inhibitor. Mod Probl Pharmacopsychiatry 19: 231–245.
Da Prada M, Kettler R, Burkard WP, Haefely WE (1984) Moclobemide, an antidepressant with short-lasting MAO-A inhibition: brain catecholamines and tyramine pressor effects in rats. In: Tipton KF, Dostert P, Strolin Benedetti M (eds) Monoamine oxidase and disease. London, Academic Press, pp 137–154.
Da Prada M, Kettler R, Keller HH, Kyburz E, Haefely WE (1987) Ro 19-6327, a novel highly selective and reversible MAO-B inhibitor. Pharmacol Toxciol 60 [Suppl 1]: 10.
Da Prada M, Kettler R, Cesura AM, Richards JG (1988a) Reversible, enzyme-activated monoamine oxidase inhibitors: new advances. Pharm Res Comm 20 [Suppl 4]: 21–33.
Da Prada M, Kettler R, Keller HH, Burkard WP (1988 b) Ro 19-6327, a reversible, highly selective inhibitor of type B monoamine oxidase, completely devoid of tyramine-potentiating effects: comparison with selegiline. In: Sandler M, Dahlström A, Belmaker RH (eds) Progress in catecholamine research, part B. Central aspects. Alan R Liss, New York, pp 359–363.
Da Prada M, Kettler R, Zürcher G, Keller HH (1988c) Hemmer der MAO-B and COMT: Möglichkeiten ihrer Anwendung bei der Parkinson-Therapie aus heutiger Sicht. In: Fischer PA (Hrsg) Modifizierende Faktoren bei der Parkinson-Therapie. Editiones Roche, Basle, S 309–322.
Da Prada M, Kettler R, Keller HH, Burkard WP, Muggli-Maniglio D, Haefely WE (1989) Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A. J Pharmacol Exp Ther 248: 400–414.
Dostert PL, Strolin Benedetti M, Tipton KF (1989) Interactions of monoamine oxidase with substrates and inhibitors. Med Res Rev 9: 45–89.
Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17: 1285–1297.
Kan JP, Steinberg R, Mouget-Goniot C, Worms P, Bizière K (1987) SR 95191, a selective inhibitor of type A monoamine oxidase with dopaminergic properties. II. Biochemical characterization of monoamine oxidase inhibition. J Pharmacol Exp Ther 240: 251–258.
Keller HH, Kettler R, Keller G, Da Prada M (1987) Short-acting novel MAO inhibitors: in vitro evidence for the reversibility of MAO inhibition by moclobemide and Ro 16-6491. Naunyn-Schmiedebergs Arch Pharmacol 335: 12–20.
Kyburz E (1988) New developments in the field of monoamine oxidase inhibitors (MAO-I). In: Van der Goot H, Domany G, Pallos L, Timmerman H (eds) Trends in medicinal chemistry 188. Elsevier, Amsterdam, pp 523–542.
Lipper S, Murphy DL, Slater S, Buchsbaum MS (1979) Comparative behavioural effects of clorgyline and pargyline in man. A preliminary evaluation. Psychopharmacology 62: 123–128.
Morier E, Helgonalch AL, Poisson M, Huchez PH, Rips R (1984) Abstract 1997P, TUPHAR 9th International Congress of Pharmacology, London, July 20–August 3.
Muggli D, Kettler R, Cesura A, Imhof R, Da Prada M (1988) Kinetic isotope effect of the reversible deuterated MAO-B inhibitor Ro 16-6491. Pharm Res Comm 20 [Suppl 4]: 121–122.
Oelschläger H, Temple DJ (1978) The role of N-oxidation in the metabolism of morpholine containing drugs. In: Gorrod JW (ed) Biological oxidation of nitrogen. Elsevier North-Holland, Amsterdam, pp 71–82.
Olsson SO, Schrold J (1971) A comparison of FG 5310, a new selective monoamine oxidase inhibitor, and other MAO inhibitors on the blood pressure response to tyramine. Acta Pharmacol Toxicol 29 [Suppl 4]: 51.
Parnham MJ, Bruinvels J (1983) Discovery in pharmacology, psycho-and neurophar-macology. Elsevier, Amsterdam.
Richards JG, Saura Marti J, Cesura AM, Da Prada M (1988) Quantitative enzyme radioautography with [3H]Ro 19-6327: localization of MAO-B in rat CNS, peripheral organs and human brain. Pharm Res Comm 20 [Suppl 4]: 91–92.
Squires RF, Lassen JB (1968) Some pharmacological and biochemical properties of γ-morpholino-butyrophenone (NSD 2023), a new monoamine oxidase inhibitor. Biochem Pharmacol 17: 369–384.
Strolin Benedetti M, Dostert P, Boucher T, Guffroy C (1982) A new reversible, selective type B monoamine oxidase inhibitor: MD 780236. In: Kamijo K, Usadin E, Nagatsu T (eds) Monoamine oxidase. Basic and clinical frontiers. Amsterdam, Excerpta Medica, pp 209-220.
Westlund KN, Denney RM, Kochsperger LM, Rose RM, Abell CW (1985) Distinct MAO A and MAO B populations in the primate brain. Science 230: 181–183.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1990 Springer-Verlag
About this chapter
Cite this chapter
Da Prada, M. et al. (1990). From moclobemide to Ro 19-6327 and Ro 41-1049: the development of a new class of reversible, selective MAO-A and MAO-B inhibitors. In: Youdim, M.B.H., Tipton, K.F. (eds) Neurotransmitter Actions and Interactions. Journal of Neural Transmission, vol 29. Springer, Vienna. https://doi.org/10.1007/978-3-7091-9050-0_27
Download citation
DOI: https://doi.org/10.1007/978-3-7091-9050-0_27
Publisher Name: Springer, Vienna
Print ISBN: 978-3-211-82142-8
Online ISBN: 978-3-7091-9050-0
eBook Packages: Springer Book Archive