CGP 28014, a new inhibitor of cerebral catechol-O-methylation with a non-catechol structure.
CGP 28014 (N-(2-pyridone-6-yl)-N',N'-di-n-propylformamidine) or its methanesulfonate salt CGP 28014 A was suspected to be a catechol-O-methyl-transferase (COMT) inhibitor because it was found to reduce the levels of homovanillic acid (HVA) and to increase those of 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat striatum, after oral or intraperitoneal administration. These effects were maintained after repeated administration. The compound was only weakly active as a COMT inhibitor in vitro. However, its effect on striatal HVA and DOPAC was not prevented by pretreatment with the inhibitor of microsomal drug metabolizing enzymes in the liver, proadifen, indicating that, if CGP 28014 acts as a prodrug, its conversion to the active compound is not by oxidative metabolism in the liver. Also, there was no evidence that conversion to 2-amino-6-hydroxypyridine could explain its effects. The in vivo effect of CGP 28014 was substantiated in two additional in vivo test systems. Thus, it inhibited the accumulation of 3-methoxytyramine in the rat striatum after MAO inhibition by clorgyline, and the formation of O-methyl-DOPA from exogenously administered DOPA. It proved to be equipotent or nearly so with tropolone, and also showed a similar duration of action. Similar to tropolone, it increased S-adenosylmethionine levels in the striatum. Pyrogallol, on the other hand, decreased them, because being a substrate of COMT, it consumes methyl groups. This suggests that CGP 28014 does not inhibit COMT because it is a substrate of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
Waldmeier
P C
PC
Research Department, Ciba-Geigy Ltd., Basel, Switzerland.
Baumann
P A
PA
Feldtrauer
J J
JJ
Hauser
K
K
Bittiger
H
H
Bischoff
S
S
von Sprecher
G
G
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000378:metabolism*; D003010:Clorgyline / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008745:Methylation; D008750:Methyldopa / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D011748:Pyrogallol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014334:Tropolone / Q000494:pharmacology
D000578:Amidines; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D018377:Neurotransmitter Agents; D011728:Pyridones; D011748:Pyrogallol; D015102:3,4-Dihydroxyphenylacetic Acid; C067181:N-(2-pyridone-6-yl)-N',N'-di-n-propylformamidine; D008750:Methyldopa; D014334:Tropolone; D003010:Clorgyline; D006719:Homovanillic Acid