318 2. ANALOGS OF ENZYME REACTION COMPONENTS 



evident and led to the conclusion that an action other than decarboxylase 

 inhibition is involved, this probably being an interference with the binding 

 of amines in the tissues. Since the a-methylamino acid analogs can be 

 slowly decarboxylated to the corresponding a-methylamines in the body, 

 and since these amines have the ability to deplete norepinephrine, it was 

 suggested that at least part of the tissue amine lowering is due to displace- 

 ment by the a-methyl analogs of the amines. This mechanism has been 

 subscribed to by several recent workers. Maitra and Staehelin (1963) ad- 

 ministered a-methyldopa to rats and guinea pigs and found the cardiac 

 catecholamine levels to be insignificantly altered. They detected an increase 

 in the a-methylnorepinephrine level, however, and a corresponding de- 

 crease in norepinephrine, indicating the displacement of the normal catechol- 

 amine with its analog. MuschoU and Maitra (1963) further demonstrated 

 that a-methylnorepinephrine stored in the sympathetic nerve endings is 

 released by nerve stimulation and is active on various adrenergic receptors. 

 Pletscher et al. (1964) after injecting a-methyldopa into rats, found marked 

 reduction of brain serotonin several hours later and felt that inhibition of 

 the decarboxylase could not explain the results. They inclined to the view 

 that a-methyldopa must also release or displace stored amines, and might 

 also interfere with the uptake of amino acids by the brain. However, S. E. 

 Smith (1963) had shown that a-methyldopa is only a very weak inhibitor 

 of 5-hydroxy tryptophan uptake in brain slices (50% inhibition at 6.7 vaM), 

 although it inhibits the decarboxylase potently (50% inhibition at 0.00056 

 mM). It may be noted that other analogs may inhibit uptake more than 

 decarboxylation. Day and Rand (1964) showed that a-methyldopa can 

 restore the activity in animals whose catecholamine levels have been de- 

 pleted by treatment with reserpine, presumably by the formation of a- 

 methylnorepinephrine, which is generally only 1/9-1/2 as pharmacologically 

 potent as norepinephrine; this does not provide direct evidence for the 

 mechanism of inhibition by a-methyldopa, but clearly shows that it forms 

 an active amine analog. 



The principles involved in the interpretation of these results are impor- 

 tant in the general field of analog inhibition and the disturbances produced 

 in tissue function, and, furthermore, the foregoing experiments might be 

 carelessly construed as invalidating the decarboxylase inhibition mechanism; 

 thus some critical comments may not be out of place. 



(1) It is unfortunate that Porter etal. (1961) did not determine decarbox- 

 ylase inhibition in brain and heart for comparison with amine depletion 

 in these tissues, since the inhibition in kidney may be quite different. In 

 the first place, the penetration of the analogs into the three tissues may 

 vary. Indeed, Hess et al. (1961) found that a-methyldopa concentrations 

 in brain, heart, and kidney are in the ratio 1:1.66:3.28 at 1 hr and 1:1.8:9.8 

 at 5 hr after injection. The concentrations of the other analogs in the tis- 



