Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 327, Issue 4, pp 273–278 | Cite as

Inhibition of monoamine oxidase and semicarbazide-sensitive amine oxidase by mexiletine and related compounds

  • Märit Eriksson
  • Christopher J. Fowler


The in vitro inhibition by mexiletine and related compounds of the activity of rat brain, heart and lung mono-amine oxidase-A (MAO-A), rat brain MAO-B, human platelet-poor plasma benzylamine oxidase and a clorgyline-resistant, semicarbazide-sensitive amine oxidase (SSAO) distinct from both MAO and benzylamine oxidase has been studied. The compounds were most active towards MAO-A and SSAO. IC50 values for mexiletine towards rat heart MAO-A and SSAO were 10 μmol/l and 320 μmol/l, respectively. Replacement of the para-hydrogen atom in the mexiletine aromatic ring by bromine increased potency towards both MAO-A and SSAO. Replacement of the ortho-methyl group in the mexiletine aromatic ring by hydrogen increased the potency towards SSAO alone. FLA 1042, with both these substitutions, was found to be a reversible mixed-type inhibitor of both MAO-A (Kislope1.4 μmol/l, Kiint24 μmol/l) and of SSAO (Kislope12 μmol/l, Kiint6 μmol/l).

Key words

Monoamine oxidase Benzylamine Mexiletine Clorgyline Amine oxidase Semicarbazide 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barrand MA, Callingham BA (1982) Monoamine oxidase activities in brown adipose tissue of the rat: some properties and subcellular distribution. Biochem Pharmacol 31:2177–2184Google Scholar
  2. Blaschko H (1974) The natural history of amine oxidases. Rev Physiol Biochem Pharmacol 70:83–148Google Scholar
  3. Buffoni F (1983) Biochemical pharmacology of amine oxidases. Trends Pharmacol Sci 4:313–315Google Scholar
  4. Callingham BA (1977) Substrate selective inhibition of monoamine oxidase by mexiletine. Br J Pharmacol 61:118P-119PGoogle Scholar
  5. Callingham BA (1982) Resolution of amine oxidase activities by irreversible inhibitors. In: Kamijo K, Usdin E, Nagatsu T (eds) Monoamine oxidase — basic and clinical frontiers. Excerpta Medical, Amsterdam, pp 100–111Google Scholar
  6. Callingham BA, Oguchi E, Oguchi K (1983) Monoamine oxidase activities in rat mesenteric arteries and veins. Br J Pharmacol 79:302PGoogle Scholar
  7. Clarke DE, Lyles GA, Callingham BA (1982) A comparison of cardiac and vascular clorgyline-resistant amine oxidase and monoamine oxidase. Inhibition by amphetamine, mexiletine and other drugs. Biochem Pharmacol 31:27–35Google Scholar
  8. Coquil JF, Goridis C, Mack G, Neff NH (1973) Monoamine oxidase in rat arteries: evidence for different forms and selective localisation. Br J Pharmacol 48:590–599Google Scholar
  9. Del Carmen Urdin M, Fuentes JA (1983) Enzyme activity of an amine oxidase resistant to pargyline in the cardiovascular system of hypertensive rats. Biochem Pharmacol 32:2345–2347Google Scholar
  10. Donnelly CH, Murphy DL (1976) Substrate- and inhibitor-related characteristics of human platelet monoamine oxidase. Biochem Pharmacol 26:953–858Google Scholar
  11. Emerole GO (1982) Benzylamine oxidase activity in rat embryo and placenta at organogenesis. Enzyme 28:396–399Google Scholar
  12. Fouts JR, Blanksma LA, Carbon JA, Zeller EA (1957) Amine oxidases. XIII. Monoamines as substrates of diamine oxidase. J Biol Chem 225:1025–1031Google Scholar
  13. Fowler CJ, Callingham BA (1977) The effect of age and thyroid hormones upon the ability of the chick heart to deaminate monoamines. J Pharm Pharmacol 29:593–597Google Scholar
  14. Fowler CJ, Strolin Benedetti M (1983) The metabolism of dopamine by both forms of monoamine oxidase in the rat brain and its inhibition by cimoxatone. J Neurochem 40:1534–1541Google Scholar
  15. Fowler CJ, Tipton KF (1984) On the substrate specificities of the two forms of monoamine oxidase. J Pharm Pharmacol 36:111–115Google Scholar
  16. Fowler CJ, Eriksson M, Thorell G, Magnusson O (1984) Stereoselective inhibition of monoamine oxidase and semicarbazide-sensitive amine oxidase by 4-dimethylamino-2,α-dimethylphenethylamine (FLA 336). Naunyn-Schmiedeberg's Arch Pharmacol 327:279–284Google Scholar
  17. Guffroy C, Fowler CJ, Strolin Benedetti M (1983) The deamination of n-pentylamine by monoamine oxidase and a semicarbazide-sensitive amine oxidase of rat heart. J Pharm Pharmacol 35:416–420Google Scholar
  18. Hall DWR, Logan BW, Parsons GH (1969) Further studies on the inhibition of monoamine oxidase by M & B 9302 (clorgyline). I. Substrate specificity in various mammalian species. Biochem Pharmacol 18:1447–1454Google Scholar
  19. Hayes BE, Counts DF, Kelley J, Clarke DE (1983) A study of amine oxidases in bleomycin-induced pulmonary fibrosis. Biochem Pharmacol 32:2347–2350Google Scholar
  20. Houslay MD, Tipton KF (1975) Inhibition of beef plasma amine oxidase by clorgyline. Biochem Pharmacol 24:429–431Google Scholar
  21. Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17:1285–1297Google Scholar
  22. Kinemuchi H, Morikawa F, Tajima H, Kamijo K (1982) Enzymatic characteristics of a clorgyline- and deprenyl-resistant amine oxidase in human plasma. In: Kamijo K, Usdin E, Nagatsu T (eds) Monoamine oxidase — basic and clinical frontiers. Excerpta Medica Amsterdam, pp 112–124Google Scholar
  23. Knoll J, Magyar K (1972) Some puzzling pharmacological effects of monoamine oxidase inhibition. Adv Biochem Psychopharmacol 5:393–408Google Scholar
  24. Kumar Y, Florvall L, Ask A-L, Ross SB, Holm A-C, Ögren S-O (1983) Selective monoamine oxidase inhibitors. Compounds derived from phenythylamine and 1-phenoxy-2-aminopropane. Acta Pharm Suec 20:349–364Google Scholar
  25. Lewinsohn R (1977) Human serum amine oxidase. Enzyme activity in severely burnt patients and in patients with cancer. Clin Chim Acta 81:247–256Google Scholar
  26. Lewinsohn R, Böhm K-H, Glover V, Sandler M (1978) A benzylamine oxidase distinct from monoamine oxidase-B — wide-spread distribution in man and rat. Biochem Pharmacol 27:1857–1863Google Scholar
  27. Lyles GA, Callingham BA (1975) Evidence for a clorgyline-resistant monoamine metabolising activity in the rat heart. J Pharm Pharmacol 27:682–691Google Scholar
  28. Lyles GA, Callingham BA (1981) The effect of DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) on monoamine oxidase activities in tissues of the rat. J Pharm Pharmacol 33:632–638Google Scholar
  29. Lyles GA, Callingham BA (1982) In vitro and in vivo inhibition by benserazide of clorgyline-resistant amine oxidases in rat cardiovascular tissues. Biochem Pharmacol 31:1417–1424Google Scholar
  30. Lyles GA, Garcia-Rodruigez J, Callingham BA (1983) Inhibitory actions of hydralazine upon monoamine oxidizing enzymes in the rat. Biochem Pharmacol 32:2515–2521Google Scholar
  31. Norqvist A, Fowler CJ, Oreland L (1981) The deamination of monoamines by pig dental pulp. Biochem Pharmacol 30:403–409Google Scholar
  32. Norqvist A, Oreland L, Fowler CJ (1982) Some properties of monoamine oxidase and a semicarbazide sensitive amine oxidase capable of the deamination of 5-hydroxytryptamine from porcine dental pulp. Biochem Pharmacol 31:2739–2744Google Scholar
  33. Otsuka S, Kobayashi Y (1964) A radioisotopic assay for mono-amine oxidase determinations in human plasma. Biochem Pharmacol 13:995–1006Google Scholar
  34. Parkinson D, Lyles GA, Browne BJ, Callingham BA (1980) Some factors influencing the metabolism of benzylamine by type A and B monoamine oxidase in rat heart and liver. J Pharm Pharmacol 32:844–850Google Scholar
  35. Strolin Benedetti M, Boucher Th, Carlsson A, Fowler CJ (1983) Intestinal metabolism of tyramine by both forms of monoamine oxidase in the rat. Biochem Pharmacol 32:47–52Google Scholar
  36. Suzuki O, Katsumata Y, Oya M (1982) Substrate specificity of type A and type B monoamine oxidase. In: Kamijo K, Usdin E, Nagatsu T (eds) monoamine oxidase — basic and clinical frontiers. Excerpta Medica, Amsterdam, pp 74–86Google Scholar
  37. Tabor CW, Tabor H, Rosenthal SM (1954) Purification of amine oxidase from beef plasma. J Biol Chem 208:645–661Google Scholar

Copyright information

© Springer-Verlag 1984

Authors and Affiliations

  • Märit Eriksson
    • 1
  • Christopher J. Fowler
    • 1
  1. 1.Research and Development LaboratoriesAstra Läkemedel ABSödertäljeSweden

Personalised recommendations