Structural studies of condensation products of biogenic amines as inhibitors of tryptophan hydroxylase.
The effects of condensation products of dopamine and indoleamines on the activity of tryptophan hydroxylase (TPH) were evaluated to determine the structures associated with modulation of this enzyme activity. The compounds having a catechol structure, such as 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, markedly inhibited the activity of the enzyme prepared from the rat brain. The inhibition was non-competitive in terms of both the biopterin cofactor and the substrate L-tryptophan. Substitution on the one or two positions of catechol isoquinolines did not affect the inhibitory activity towards TPH. Among these compounds, a charged substance, 1,2[N]-dimethyl-6,7-dihydroxy-isoquinolinium ion, was an extremely potent inhibitor; the Ki values were 0.88 +/- 0.17 and 0.64 +/- 0.08 microM (mean +/- S.D.) in terms of the substrate and cofactor, respectively. By contrast, the condensation products of tryptophan and tryptamine with acetaldehyde scarcely affected TPH activities. 1-Methyl-1,2,3,4-tetrahydroisoquinoline, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ion (MPP+) were almost inactive. These results indicated that the catechol structure recognized and combined with TPH at a binding site different from that of the substrate or cofactor and the positive charge on the dopamine-derived substance enhanced the affinity to TPH. The selective inhibition of TPH by dopamine-derived catechol isoquinolines was discussed in relationship to the interactions between catecholamines, indoleamines and their metabolites in the brain under physiological and pathological conditions.
Matsubara
K
K
Department of Legal Medicine, Shimane Medical University, Izumo, Japan.
Ota
M
M
Takahashi
T
T
Maruyama
W
W
Naoi
M
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D001679:Biogenic Amines / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004298:Dopamine / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D014364:Tryptophan / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors*
D001679:Biogenic Amines; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; D014364:Tryptophan; C036617:salsolinol; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014365:Tryptophan Hydroxylase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine