Psychopharmacology

, Volume 106, Supplement 1, pp S6–S14 | Cite as

Biochemistry and pharmacology of moclobemide, a prototype RIMA

  • W. Haefely
  • W. P. Burkard
  • A. M. Cesura
  • R. Kettler
  • H. P. Lorez
  • J. R. Martin
  • J. G. Richards
  • R. Scherschlicht
  • M. Da Prada
Section I RIMA: Pharmacology, Biochemistry And Interactions

Abstract

RIMA is a term for reversible inhibitors of monoamine oxidase (MAO) with preference for MAO-A; moclobemide is a prototype of this new class of antidepressants and is a highly selective inhibitor of MAO-A in vitro. This inhibition is reversible by dialysis in vitro, which accounts for the dose-dependent duration of in vivo enzyme inhibition of 12–24 h. Moclobemide increases the content of serotonin, noradrenaline and dopamine in the brain, and decreases that of their deaminated metabolites. Its biochemical, neurological and behavioural effects indicate that it increases the extracellular concentration of the classic monoamine neurotransmitters/neuromodulators — in particular 5-HT. Potentiation of the cardiovascular effects of tyramine is less pronounced after taking moclobemide than after irreversible MAO-A inhibitors. Understanding of the physiological role of MAO and of the events that link inhibition of the enzyme with modulation of neuronal activities in the CNS remains incomplete. A major physiological role of intraneuronal MAO is to keep cytosolic amine concentration very low, to enable the neuronal monoamine carriers to produce a net inward transport of monoamines, and thereby to act as the first step in the termination of action of extracellular monoamines. MAO is likely to have a similar function in non-monoaminergic cells with respect to the monoamine carriers they contain. In addition to the classic monoamines, “trace” amines may become functionally active after MAO inhibition. An alternative role for MAO is that of a scavenger, preventing natural substrates from accumulating in monoaminergic neurons and interacting with storage, release, uptake and receptor function of monoamines.

Key words

MAO-A inhibitor Moclobemide Antidepressant biochemistry Pharmacology Monoamines 

References

  1. Bielenberg GW, Burkhardt M (1990) 5-Hydroxytryptamine1A agonist. A new therapeutic principle for stroke treatment. Stroke 21 [suppl IV]:161–163Google Scholar
  2. Bönisch H, Trendelenburg U (1988) The mechanism of action of indirectly acting sympathomimetic amines. Handbook of Experimental Pharmacology 90/I:247–277Google Scholar
  3. Burkard WP, Kettler R, Da Prada M, Haefely WE (1988) Neurochemical profile of the antidepressant moclobemide, a reversible type A monoamine oxidase inhibitor with minimal tyramine maker RH (eds) Neurology and neurobiology, vol 42 B. A.R. Liss, New York, pp 168–171Google Scholar
  4. Burkard WP, Da Prada M, Keller HH, Kettler R, Haefely W (1989a) Preclinical pharmacology of moclobemide. A review of published studies. Br J Psychiatry 155 [suppl]:84–88Google Scholar
  5. Burkard WP, Bonetti EP, Da Prada M, Martin JR, Polc P, Schaffner R, Scherschlicht R, Hefti F, Müller RKM, Wyss P-C, Haefely W (1989b) Pharmacological profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A. J Pharmacol Exp Ther 248:391–399Google Scholar
  6. Carney JM (1986) Acute tryptophan pretreatment protects against behavioral changes caused by cerebral ischemia. Neurosci Lett 66:127–130Google Scholar
  7. Cesura AM, Kettler R, Imhof R, Da Prada M (1992) Mode of action and characteristics of monoamine oxidase-A inhibition by moclobemide. Psychopharmacology [suppl] 106:S15-S16Google Scholar
  8. Da Prada M, Keller HH, Kettler R, Schaffner R, Pieri M, Burkard WP, Korn A, Haefely WE (1981) Ro 11-1163, a specific and short-acting MAO inhibitor with antidepressant properties. In: Kamijo K, Usdin E, Nagatsu T (eds) Monoamine oxidase. Basic and clinical frontiers. Excerpta Medica, Elsevier, Amsterdam-Oxford-Princeton, pp 183–196Google Scholar
  9. 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. Academic Press, London, pp 137–154Google Scholar
  10. Da Prada M, Zürcher G, Wüthrich I, Haefely WE (1988) On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. J Neural Transm [suppl] 26:31–56Google Scholar
  11. Da Prada M, Kettler R, Keller HH, Burkard WP, Haefely WE (1989a) Preclinical profiles of the novel reversible MAO-A inhibitors, moclobemide and brofaromine, in comparison with irreversible MAO inhibitors. J Neural Transm [suppl] 28:5–20Google Scholar
  12. Da Prada M, Kettler R, Keller HH, Burkard WP, Muggli-Maniglio D, Haefely WE (1989b) Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A. J Pharmacol Exp Ther 248:400–414Google Scholar
  13. Da Prada M, Keller HH, Kettler R (1989c) Vergleich des neuen MAO-A-Hemmers Moclobemid, Brofaromin und Toloxaton mit Tranylcypromin im Tierversuch: Bedeutung für die Praxis. Psychiatr Prax 16:18–24Google Scholar
  14. Da Prada M, Kettler R, Keller HH, Cesura AM, Richards JG, Saura Marti J, Muggli-Maniglio D, Wyss P-C, Kyburz E, Imhof R (1990a) From moclobemide to Ro 19-6327 and Ro41-1049: the development of a new class of reversible, selective MAO-A and MAO-B inhibitors. J Neural Transm Suppl 29:279–292Google Scholar
  15. Da Prada M, Kettler R, Keller HH, Burkard WP (1990b) Short-lasting and reversible inhibition of monoamine oxidase-A by moclobemide. Acta Psychiatr Scand [suppl] 360:103–105Google Scholar
  16. Flack B, Hillarp N-A, Thieme G, Torp A (1962) Fluorescence of catecholamines and related compounds condensed with formaldehyde. J Histochem Cytochem 10:348–354Google Scholar
  17. Fuxe K, Agnati LF (eds) (1990) Volume transmission in the brain. Raven Press, New YorkGoogle Scholar
  18. Gleiter CH, Nilsson E, Antonin KH, Bieck PR (1990) Effect of MAO inhibitors (brofaromine, clorgyline and moclobemide) on human platelet MAO-B activity. Clin Pharmacol Ther 47:165Google Scholar
  19. Graefe K-H, Bönisch H (1988) The transport of amines across the axonal membranes of noradrenergic and dopaminergic neurons. Handbook of Experimental Pharmacology 90/I:193–245Google Scholar
  20. 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. Arch Pharmacol 335:12–20Google Scholar
  21. Korn A, Da Prada M, Rafferberg W, Allen S, Gasic S (1988a) Tyramine pressor effect in man: studies with moclobemide, a novel, reversible monoamine oxidase inhibitor. J Neural Transm [suppl] 26:57–71Google Scholar
  22. Korn A, Da Prada M, Rafferberg W, Gasic S, Eichler HG (1988b) The effect of moclobemide, a new reversible monoamine oxidase inhibitor, on absorption and pressor effect of tyramine. J Cardiovasc Pharmacol 11:17–23Google Scholar
  23. Kwan S-W, Bergeron JM, Abell CW (1992) Molecular properties of monoamine oxidases A and B. Psychopharmacology [suppl] 106:S1-S5Google Scholar
  24. Kyburz E (1989) New developments in the field of monoamine oxidase inhibitors (MAO-I). In: van der Goot H, Pallos L, Timmerman H (eds) Trends in Medicinal Chemistry 88. Elsevier, Amsterdam, pp 523–542Google Scholar
  25. Lorez HP, Harvey J, Blaszat G, Thomas B, Martin JR, Kettler R, Wybrecht R, Da Prada M (1990) Inhibition of type A monoamine oxidase of hypoxic rat brain results in neuroprotection. Eur J Neurosci 3:133Google Scholar
  26. Martin JR, Schaffner R, Rumennik L, Vincent GP, Sepinwall J, Lorez H-P, Haefely WE (1989) Cognitive performance enhancing effects of the reversible MAO-inhibitor moclobemide in animals. In: Wurtman RJ, Corkin S, Growdon JH, Ritter-Walker E (eds) Alzheimer's disease. Center for Brain Sciences and Metabolism Charitable Trust, Cambridge, MA, pp 689–694Google Scholar
  27. Paterson IA, Inorio AV, Boulton AA (1990) 2-Phenylethylamine: a modulator of catecholamine transmission in the mammalian central nervous system? J Neurochem 55:1827–1837Google Scholar
  28. Richards JG, Saura J, Ulrich J, Da Prada M (1992) Molecular neuroanatomy of monoamine oxidases in human brainstem. Psychopharmacology [suppl] 106:21–23Google Scholar
  29. Saavedra JM (1989) β-Phenylethylamine, phenylethanol-amine, tyramine and octopamine. Handbook of Experimental Pharmacology 90/II:181–210Google Scholar
  30. Scheinin M, Koulu M, Karhuvaara S, Zimmer RH (1990) Evidence that the reversible MAO-A inhibitor moclobemide increases prolactin secretion by a serotonergic mechanism in healthy male volunteers. Life Sci 47:1491–1499Google Scholar
  31. Scherschlicht R, Polc P, Schneeberger J, Steiner M, Haefely W (1982) Selective suppression of rapid eye movement sleep (REMS) in cats by typical and atypical antidepressants. In: Costa E, Racagni G (eds) Typical and atypical antidepressant. Raven Press, New York, pp 354–364Google Scholar
  32. Schoerlin M-P, Da Prada M (1990) Species-specific biotransformation of moclobemide: a comparative study in rats and humans. Acta Psychiatr Scand [suppl] 360:108–110Google Scholar
  33. Shih JC (1991) Molecular basis of human MAO-A and B. Neuropsychopharmacology 4:1–7Google Scholar
  34. Trendelenberg U, Cassi L, Grohmann M, Lengeloh A (1987) The functional coupling of neuronal and extraneuronal transport with intracellular monoamine oxidase. J Neural Transm [suppl] 23:91–101Google Scholar
  35. Trendelenburg U (1988) The extraneuronal uptake and metabolism of catecholamines. Handbook of Experimental Pharmacology 90/I:279–319Google Scholar
  36. Weyler W, Hsu Y-PP, Breakefield XO (1990) Biochemistry and genetics of monoamine oxidase. Pharmacol Ther 47:391–417Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • W. Haefely
    • 1
  • W. P. Burkard
    • 1
  • A. M. Cesura
    • 1
  • R. Kettler
    • 1
  • H. P. Lorez
    • 1
  • J. R. Martin
    • 1
  • J. G. Richards
    • 1
  • R. Scherschlicht
    • 1
  • M. Da Prada
    • 1
  1. 1.Pharmaceutical Research Department CNSF. Hoffmann-La Roche LtdBaselSwitzerland

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