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

J Neural Transm Suppl. 1990;29:279-92. doi: 10.1007/978-3-7091-9050-0_27.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Benzamides / pharmacology*
  • Brain / drug effects
  • Brain / enzymology*
  • Enzyme Inhibitors / pharmacology*
  • Moclobemide
  • Monoamine Oxidase / metabolism*
  • Picolinic Acids / pharmacology*
  • Rats
  • Thiazoles / pharmacology*

Substances

  • Benzamides
  • Enzyme Inhibitors
  • Picolinic Acids
  • Thiazoles
  • Ro 41-1049
  • lazabemide
  • Monoamine Oxidase
  • Moclobemide