α‐DIFLUOROMETHYL DOPA, A NEW ENZYME‐ACTIVATED IRREVERSIBLE INHIBITOR OF AROMATIC L‐AMINO ACID DECARBOXYLASE

Abstract DL‐x‐Difluoromethyl DOPA (DFMD, RMI 71801), an enzyme‐activated irreversible inhibitor of aromatic L‐amino acid decarboxylase in vitro, produces a rapid, long‐lasting and dose‐dependent inhibition of aromatic L‐amino acid decarboxylase in peripheral tissues of mice when administered i.p. or orally. Doses of 500 mg/kg i.p. produce only very slight inhibition of the enzyme activity in mouse brain whilst inhibiting the enzyme activity of peripheral tissues by more than 90%. With L‐[3H]‐DOPA co‐administration brain concentrations of L‐[3H]DOPA and 3H‐catecholamines are increased 3‐ to 8‐fold concomitant with a decrease in the peripheral decarboxylation of L‐[3H]DOPA. Under these conditions it is clear that the slight inhibition of enzyme activity in the brain is totally inadequate to inhibit the decarboxylation of L‐DOPA in this organ. Similarly, the decarboxylation of exogenously supplied 5‐hydroxytryptophan is inhibited peripherally with a consequent increase in brain serotonin concentrations. DFMD is another example of an enzyme‐activated irreversible inhibitor which due to its novel and specific mechanism of action, may offer advantages over existing decarboxylase inhibitors.