316 



2. ANALOGS OF ENZYME REACTION COMPONENTS 



100 



75 



50 



25- 



% OF 

 NORMAL 



20 



time (HOURS) — 



40 



60 



80 



100 



Fig. 2-4. Effects of a-methyl-w-tyrosine on brain amine concentrations in the 

 guinea pig following an intraperitoneal dose of 400 mg/kg. (From Hess e< a?., 1961.) 



and remains at a lower level for a longer time than in brain. The results 

 on serotonin and dopamine levels in the brain correspond as expected to 

 the time course of decarboxylase inhibition, but the prolonged depletion 

 of norepinephrine is difficult to explain on this basis. Since dopamine levels 

 return to normal long before norepinephrine, there must be either an in- 

 hibition of the /?-hydroxylation of dopamine to norepinephrine or an in- 

 terference with the tissue binding of norepinephrine. Hess et al. (1961) 

 showed that these analogs inhibit /5-hydroxyIation only at relatively high 

 concentrations, which might have been produced soon after injection but 

 certainly would not occur several hours later, and thus inclined to the sec- 

 ond explanation. The lack of inhibition of dopamine /5-oxidase has been 

 confirmed by Creveling et al. (1962) 



The time course for catecholamine depletion in mouse brain and heart 

 following administration of these analogs is similar to that following re- 

 serpine, except the return toward normal in the brain is somewhat faster. 

 Porter et al. (1961) examined different analogs for ability to reduce nor- 

 epinephrine in the brain and heart, and compared these results with their 

 effectiveness in inhibiting decarboxylation of 5-hydroxytryptophan in 

 kidney (Table 2-12). Some lack of correlation between the two activities is 



