314 2. ANALOGS OF ENZYME REACTION COMPONENTS 



inhibitory activity increases with the length or bulk of the side chain. 

 Also it may be noted that the Hnear cinnamate derivatives are generally 

 more potent than the hydrocinnamates. One must conclude that the most 

 important binding groups are the hydroxyls, the ring, the side-chain car- 

 bonyl, and any more terminal groups, which just about includes all of the 

 molecule. The specificity of these inhibitors may well be quite high, since 

 3-hydroxycinnamate and 3,4-dihydroxycinnamate (caffeate) were tested 

 on tyrosine decarboxylase, glutamate decarboxylase, histidine decarbo- 

 xylase, and succinate dehydrogenase, and found to be without effect. 

 Tyrosinase is inhibited somewhat, especially by caffeate. 



There is evidence in patients with phenylpyruvic oligophrenia of a dis- 

 turbance in tyrosine metabolism (hypopigmentation), and it is possible 

 that the phenyl acids which are abnormally high might be inhibiting some 

 step or steps in these pathways. Fellman (1956) therefore studied the ef- 

 fects of such substances on the dopa decarboxylase from beef adrenal 

 medulla. The order of inhibitory potency is phenylpyruvate > phenyllac- 

 tate > phenylacetate > phenylalanine. Phenylpyruvate inhibits 77% when 

 equimolar (3.3 milf ) with L-dopa. The low plasma epinephrine levels found 

 in these patients thus might be due to such an inhibition, but another point 

 of attack would have to be adduced for a suppression of melanin formation. 

 It is interesting that this enzyme is inhibited quite strongly by norepi- 

 nephrine and dopamine, whereas epinephrine exerts no effect (Fellman, 

 1959). The susceptibilities of dopa decarboxylases from various tissues 

 are obviously different, since the results of Fellman are often different 

 from those of previous workers. 



cf-Methyldopa and related analogs can effectively inhibit decarboxylases 

 in vivo, thereby interfering with amine formation and modifying tissue 

 function. Direct evidence for an in vivo inhibition was obtained by intra- 

 muscular injection of «-methyldopa into guinea pigs and demonstration 

 of a marked depression of the decarboxylation of both dopa and 5-hydroxy- 

 tryptophan in isolated kidney 15-30 min afterward (Westermann et at., 

 1958). Indeed, the inhibition of 5-hydroxytryptophan decarboxylation is 

 complete and after 90 min is 83%. More indirect evidence has been obtain- 

 ed by showing that these analogs prevent the pharmacological actions of 

 dopa and 5-hydroxytryptophan, these actions being dependent on decar- 

 boxylation of these substances to dopamine and serotonin, respectively. 

 Injection of dopa leads to a rise in the blood pressure which is probably 

 primarily due to dopamine (although some norepinephrine and epinephrine 

 may also be formed). This pressor response can be blocked by several de- 

 carboxylase inhibitors, including 5-(3-hydroxycinnamoyl)salicylate (Po- 

 grund and Clark, 1956) and a-methyldopa (Dengler and Keichel, 1958). 

 There is no effect on the response to dopamine or norepinephrine. The 

 increase in cardiac contractility induced by dopa is also completely blocked 



