EFFECTS ON THE KIDNEY 935 



(1962 b) also postulate a two-group receptor, one group being SH; mer- 

 curials which are diuretics attach to the SH group, split, and the resulting 

 Hg++ makes a two-point attachment. The block by p-MB is due to its 

 binding to the SH group; being stable it does not split. If this is so, p-MB 

 might be expected to displace mercurials in the kidney, and this was dem- 

 onstrated using Hg^^^-labeled chlormerodrin. The decrease in radioactivity 

 of the kidneys parallels the antagonism of the diuresis by p-MB. 



Another hypothesis for diuretic mechanism was outlined by Kessler et 

 al. (1957 b), who assumed that the organic mercurials act as intact molecules 

 by a two-point attachment to a receptor. The basic structure for diuretic 

 activity was given as R — C — C — C — Hg+, i.e., a hydrophilic group sepa- 

 rated from the Hg by three carbon atoms, the R group interacting in some 

 manner with a group spaced appropriately in relation to an SH group. This 

 hypothesis in its simple form has had to be abandoned in the light of fur- 

 ther work showing that various mercurials not conforming to this structure 

 are diuretic, e.g., some of the aryl mercurials (Weiner et al., 1962). How- 

 ever, the idea that there is some relationship between structure and diuretic 

 action should not be given up, inasmuch as the situation may be more com- 

 plex than originally assumed. If one considers the three simple alkyl mer- 

 curials (see accompanying tabulation), one sees that diuretic activity is 



Alky] mercurial Diuretic activity Lability 



CH3— CH2— Hg+ - - 



HO— CH2— CH2— Hg+ + + 



HO— CH2— CH2— CHj— Hg+ - - 



correlated with acid lability, and that HO— CH2CH2CH2— Hg+, which 

 should be diuretic in the scheme of Kessler et al., is not. It is intriguing 

 that HO— CH2CH2— Hg+ is 95% split under the conditions of the lability 

 test, whereas the other two compounds are completely stable; it is also 

 surprismg that HO^— Hg+ and HgN— <^— Hg+ are 73% and 88% split, 

 respectively, while "OOC — (f — Hg+ and (f — Hg+ are not split at all. The 

 structural requirements of lability seem to be very rigid. Could it be that 

 the structural requirements for splitting are the same as for combination 

 with a receptor to produce diuresis, splitting not being a necessary prelude 

 to an effect? It is clear that a final decision as to these important matters 

 cannot be reached at this time and that more data must be accumulated; 

 one would like to have some information on the rates of splitting of mer- 

 curials in homogenates or extracts of kidney, and the effects of pH on this. 



