The significance of COMT activity in controlling dopamine agonist levels in brain and serum: studies with a prodrug and a metabolite of 6,7-ADTN.
After i.p. administration of the dibenzoylester of 2-amino-6,7-dihydroxytetralin (DB-6,7-ADTN) a metabolite was found in rat brain and serum, which was identified as 2-amino-6-hydroxy-7-methoxytetralin (7-O-MeADTN). By means of HPLC coupled with amperometric detection, time-concentration curves of 7-O-MeADTN in rat brain and serum were determined after 100 mumol/kg DB-6,7-ADTN. These showed a rapid formation and homogeneous distribution of high peak levels (4 nmol/g) of 7-O-MeATN. Brain and serum concentrations of 6,7-ADTN after 100 mumol/kg DB-6,7-ADTN, determined during catechol-O-methyltransferase (COMT) inhibition by tropolone, were 5--7 times higher than those during normal COMT activity, thus equalling 5,6-ADTN concentrations after 100 mumol/kg DB-5,6-ADTN. The greater susceptibility of 6,7-ADTN to metabolic degradation by COMT was confirmed by preliminary results of in vitro studies, which showed that two methoxy derivatives are formed from 6,7-ADTN and one, in very small amounts, from 5,6-ADTN. 7-O-MeADTN had no dopaminergic activity of its own, as after i.p. injection of 100 mumol/kg it was devoid of behavioural and biochemical effects typical for DA agonists. A homogeneous distribution and high peak concentrations (20 nmol/g after 15 min) were found in rat brain after this dose of the metabolite. The results indicate that a substantial amount of 6,7-ADTN, in contrast to 5,6-ADTN, is metabolized by COMT and that differences between brain concentrations of both isomers are almost exclusively due to differences in susceptibility for COMT. This has implications for the design of new DA agonists.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry; D065098:Catechol O-Methyltransferase Inhibitors; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006719:Homovanillic Acid / Q000032:analysis; D009281:Naphthalenes / Q000032:analysis* / Q000378:metabolism*; D009284:Naphthols / Q000032:analysis* / Q000097:blood / Q000378:metabolism*; D051381:Rats; D011954:Receptors, Dopamine / Q000032:analysis / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000032:analysis* / Q000097:blood / Q000378:metabolism*; D013997:Time Factors; D014334:Tropolone / Q000494:pharmacology
D065098:Catechol O-Methyltransferase Inhibitors; D009281:Naphthalenes; D009284:Naphthols; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; D015102:3,4-Dihydroxyphenylacetic Acid; C020196:2-amino-5,6-dihydroxytetralin; C011639:ADTN; C026069:dibenzoyl 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene; C026070:2-amino-6-hydroxy-7-methoxytetralin; D014334:Tropolone; D004298:Dopamine; D006719:Homovanillic Acid