Transition-state analogues as inhibitors of L-dopa decarboxylase.

Abstract 1. 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. 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. 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. 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. 5. Inhibition was competitive with respect to l -dopa, but was neither competitive nor non-competitive with respect to pyridoxal phosphate. 6. 6. The most active compound tested was the oxazine derivative of the l -dopa/salicaldehyde adduct, with an estimated K i of 58.0μM. 7. 7. Increased inhibitory activity was observed when enzyme depleted of pyridoxal phosphate was used.