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.
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.
Da Prada
M
M
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd., Basle, Switzerland.
Kettler
R
R
Keller
H H
HH
Cesura
A M
AM
Richards
J G
JG
Saura Marti
J
J
Muggli-Maniglio
D
D
Wyss
P C
PC
Kyburz
E
E
Imhof
R
R
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020912:Moclobemide; D008995:Monoamine Oxidase / Q000378:metabolism*; D010848:Picolinic Acids / Q000494:pharmacology*; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology*
D001549:Benzamides; D004791:Enzyme Inhibitors; D010848:Picolinic Acids; D013844:Thiazoles; C063456:Ro 41-1049; C059303:lazabemide; D008995:Monoamine Oxidase; D020912:Moclobemide