Transition-state analogues as inhibitors of L-dopa decarboxylase.
1. A series of compounds has been prepared which are analogues of the transition state of the reaction catalysed by L-dopa decarboxylase (EC 4.1.1.28). 2. These compounds are reduced adducts of the substrate (L-dopa) and coenzyme (pyridoxal phosphate), as well as analogues of these substances (D-dopa, pyridoxal and salicaldehyde). 3. Compounds were also prepared with an oxazine link between the 3'-oxygen and the nitrogen attached to the 4'-carbon of the aldehyde moiety. 4. None of the D-dopa adducts produced any significant inhibition, but the L-dopa adducts were all active at millimolar levels, with the oxazine derivatives being more active than their parent compounds. 5. Inhibition was competitive with respect to L-dopa, but was neither competitive nor non-competitive with respect to pyridoxal phosphate. 6. The most active compound tested was the oxazine derivative of the L-dopa/salicaldehyde adduct, with an estimated Ki of 58.0 microM. 7. Increased inhibitory activity was observed when enzyme depleted of pyridoxal phosphate was used.
Brinkworth
R I
RI
Victorian College of Pharmacy Ltd., Parkville, Australia.
Iles
M M
MM
Iskander
M N
MN
Andrews
P R
PR
D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001665:Binding Sites; D001667:Binding, Competitive; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000145:classification*; D007668:Kidney / Q000201:enzymology; D007980:Levodopa / Q000031:analogs & derivatives*; D008962:Models, Theoretical; D011732:Pyridoxal Phosphate / Q000302:isolation & purification / Q000502:physiology; D013552:Swine
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D004791:Enzyme Inhibitors; D007980:Levodopa; D011732:Pyridoxal Phosphate