320 2. ANALOGS OF ENZYME REACTION COMPONENTS 



(4) The fact that certain a-methyl analogs of the catecholamines can 

 deplete tissues of the amines, although they do not inhibit the decarboxy- 

 lase, is not evidence against a decarboxylase inhibition mechanism for the 

 a-methylamino acids, but indicates another mechanism, which may play 

 a role in the prolonged lowering of norepinephrine levels without neces- 

 sarily being involved in the initial rapid fall in tissue amines. The relatively 

 rapid return of serotonin and dopamine levels to normal (Fig. 2-4) suggests 

 that there is no generalized disturbance in tissue amine binding, but that 

 the effect is specifically on norepinephrine. The most satisfactory position 

 at the present time might be the following: the initial marked fall in tissue 

 amines brought about by the a-methyl analogs is primarily due to an in- 

 hibition of decarboxylation (perhaps supplemented at peak concentrations 

 by inhibition of other steps, such as /?-hydroxylation), and further distur- 

 bances in amine binding are progressively produced by the a-methylamines 

 formed from the inhibitors, so that even when the decarboxylase is normally 

 active again the tissues cannot concentrate certain of the normal catechol- 

 amines. 



Dopamine p-Hydroxylase 



This enzyme catalyzes the synthesis of norepinephrine from dopamine 

 and, as we have seen, its inhibition by analogs could be both theoretically 

 and practically important. Hess et al. (1961) found that a-methyl-3-hy- 

 droxyphenylalanine does not inhibit at 2 tclM. but inhibits 50% at 4 toM. 

 The concentration of a-methyldopa 1 hr after injection is given as 376 

 //g/g in the heart and this could mean a concentration around 750 //g/ml 

 of intracellular fluid (assuming extracellular fluid has a low concentration 

 at this time). This is approximately equivalent to 4 mM so that appreciable 

 inhibition might occur. Inhibition data indicate that 3-methyl-3-hydroxy- 

 phenylalanine concentrations in the tissues are roughly the same as a- 

 methyldopa concentrations. Until more is known about the nature of the 

 inhibition of this enzyme, it might be safe to conclude that it plays some 

 role in the effects of the or-methyl analogs of phenylalanine. 



Various amines can inhibit this enzyme (Goldstein and Contrera, 1961). 

 When dopamine concentration is 0.26 niM, the following inhibitions are 

 observed: tyramine at 2.9 raM (75%), /?-phenylethylamine at 3.3 vaM 

 (45%), amphetamine at 5.9 milf (35%), and 3-methoxydopamine at 4.8 

 mM (15%). None of these inhibitors appears to be potent enough to be 

 practically important in reducing norepinephrine synthesis and, further- 

 more, these amines are so pharmacologically active that their use is limited. 

 Benzyloxy amine, and particularly the p-hydroxyl derivative, inhibit this 

 enzyme rather potently, 0.01 mM of the latter blocking almost completely 

 after 90 min (van der Schoot et al., 1963), this being attributed to the iso- 

 steric relation between phenethylamines and benzyloxyamines. 



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