BIOMAT Database Logo BIOMAT Database Logo

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. 1990

M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd., Basle, Switzerland.

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.

UI MeSH Term Description Entries
D008995 Monoamine Oxidase An enzyme that catalyzes the oxidative deamination of naturally occurring monoamines. It is a flavin-containing enzyme that is localized in mitochondrial membranes, whether in nerve terminals, the liver, or other organs. Monoamine oxidase is important in regulating the metabolic degradation of catecholamines and serotonin in neural or target tissues. Hepatic monoamine oxidase has a crucial defensive role in inactivating circulating monoamines or those, such as tyramine, that originate in the gut and are absorbed into the portal circulation. (From Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 8th ed, p415) EC 1.4.3.4. Amine Oxidase (Flavin-Containing),MAO,MAO-A,MAO-B,Monoamine Oxidase A,Monoamine Oxidase B,Type A Monoamine Oxidase,Type B Monoamine Oxidase,Tyramine Oxidase,MAO A,MAO B,Oxidase, Monoamine,Oxidase, Tyramine
D010848 Picolinic Acids Compounds with general formula C5H4N(CO2H) derived from PYRIDINE, having a carboxylic acid substituent at the 2-position. Acids, Picolinic
D001921 Brain The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM. Encephalon
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001549 Benzamides BENZOIC ACID amides.
D013844 Thiazoles Heterocyclic compounds where the ring system is composed of three CARBON atoms, a SULFUR and NITROGEN atoms. Thiazole
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D020912 Moclobemide A reversible inhibitor of monoamine oxidase type A; (RIMA); (see MONOAMINE OXIDASE INHIBITORS) that has antidepressive properties. Apo-Moclobemide,Arima,Aurorex,Aurorix,Chem mart Moclobemide,DBL Moclobemide,Deprenorm,Feraken,GenRX Moclobemide,Healthsense Moclobemide,Manerix,Moclamine,Moclix,Moclobamide,Moclobemid AZU,Moclobemid Stada,Moclobemid von ct,Moclobemid-1A Pharma,Moclobemid-Puren,Moclobemid-ratiopharm,Moclobeta,Moclodura,Moclonorm,Novo-Moclobemide,Nu-Moclobemide,PMS-Moclobemide,Rimoc,Ro 11-1163,Ro-11-1163,Terry White Chemists Moclobemide,AZU, Moclobemid,Apo Moclobemide,Moclobemid 1A Pharma,Moclobemid Puren,Moclobemid ratiopharm,Moclobemid1A Pharma,Moclobemide, Chem mart,Moclobemide, DBL,Moclobemide, GenRX,Moclobemide, Healthsense,Novo Moclobemide,NovoMoclobemide,Nu Moclobemide,NuMoclobemide,PMS Moclobemide,Ro 11 1163,Stada, Moclobemid,von ct, Moclobemid

Related Publications

M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
Effects of MAO-A and MAO-B selective inhibitors Ro 41-1049 and Ro 19-6327 on the deamination of newly formed dopamine in the rat kidney.
December 1990, The Journal of pharmacology and experimental therapeutics,
M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
Effect of type A and B monoamine oxidase selective inhibition by Ro 41-1049 and Ro 19-6327 on dopamine outflow in rat kidney slices.
December 1994, British journal of pharmacology,
M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
In vivo effects of the monoamine oxidase inhibitors Ro 41-1049 and Ro 19-6327 on the production and fate of renal dopamine.
January 1994, Journal of neural transmission. Supplementum,
M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
Effect of a selective MAO-A inhibitor (Ro 41-1049) on striatal L-dopa and dopamine metabolism: an in vivo study.
January 1994, Journal of neural transmission. Parkinson's disease and dementia section,
M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
Monoamine oxidase B (MAO B) inhibitor therapy in Parkinson's disease: the degree and reversibility of human brain MAO B inhibition by Ro 19 6327.
October 1993, Neurology,
M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
[3H]Ro 19-6327: a reversible ligand and affinity labelling probe for monoamine oxidase-B.
March 1989, European journal of pharmacology,
M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
Effect of the selective MAO-A inhibitors brofaromine, clorgyline and moclobemide on human platelet MAO-B activity.
January 1992, Journal of neural transmission. General section,
M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
Development of a Novel Class of Pyridazinone Derivatives as Selective MAO-B Inhibitors.
June 2022, Molecules (Basel, Switzerland),
M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
Pyridazinones containing dithiocarbamoyl moieties as a new class of selective MAO-B inhibitors.
October 2021, Bioorganic chemistry,
M Da Prada, and R Kettler, and H H Keller, and A M Cesura, and J G Richards, and J Saura Marti, and D Muggli-Maniglio, and P C Wyss, and E Kyburz, and R Imhof
Identification of Indole-Based Chalcones: Discovery of a Potent, Selective, and Reversible Class of MAO-B Inhibitors.
August 2016, Archiv der Pharmazie,
Copied contents to your clipboard!