504 2. ANALOGS OF ENZYME REACTION COMPONENTS 



Pyridine-3-sulfonate and Pyridine-3-sulfonamide 



These analogs might be expected to inhibit nicotinate and nicotinamide 

 metaboHsm. Both inhibit the growth of various bacteria and the inhibitions 

 can be overcome by nicotinamide (Mcllwain, 1940). Reference to the tab- 

 ulation on page 501 shows that lactate dehydrogenase is inhibited more 

 by these analogs than the corresponding nicotinic compounds, whereas glu- 

 cose dehydrogenase behaves in the opposite fashion (von Euler, 1942). 

 Feeding pyridine-3-sulfonate at 5% in the diet to mice produces no 

 signs of nicotinate deficiency, but the mouse does not require exogenous 

 nicotinate (Woolley and White, 1943 a). However, nicotinate-deficient dogs 

 are made worse by administration of the analog (Woolley et al., 1938), 

 although Gaebler and Beher (1951) observed no effect of 0.5-2 g/day of 

 pyridine-3-sulfonate on the excretion of A^-methylnicotinamide, erythrocyte 

 coenzyme level, or general health of either normal or nicotinate-deficient 

 dogs. Hicks (1955) found hippocampal necrosis in only one animal given 

 pyridine-3-sulfonate, so that it is presumably not as effective as 3-acetyl- 

 pyridine. Brain NADase is not inhibited by pyridine-3-sulfonamide (Mcll- 

 wain, 1950), and the sulfonate does not significantly inhibit either beef 

 spleen NADase (Zatman et al., 1954 a) or nicotinamide deaminase (Grosso- 

 wicz and Halpern, 1956 b). The most potently inhibited enzyme examined 

 seems to be yeast alcohol dehydrogenase, the sulfonate being the most po- 

 tent inhibitor of all the substituted pyridines (Table 2-30). There is no 

 evidence that NAD analogs can be formed from these substances. The 

 respiration of resting Mycobacterium phlei, either without substrate or with 

 glycerol, is not inhibited by 1 mM pyridine-3-sulfonate, but proliferating 

 bacterial respiration is inhibited 52-85% (almost completely by 10 niM) 

 (Miiller et al., 1960). These scattered observations do not arouse much in- 

 terest in these analogs, but perhaps the proper systems have not been 

 studied. 



6-Aminonicotinamide 



This analog has been called the most potent nicotinamide antagonist 

 available (Johnson and McCoU, 1955). The acute LD50 in mice is 35 mg/kg, 

 although 2 mg/kg/day leads to 50% mortality by the eleventh day (John- 

 son and McColl, 1956). Simultaneous administration of 50 mg/kg nicotina- 

 mide raises the LD50 8-fold. It is very toxic to rabbits, producing loss of 

 motor control and paralysis, and in rats it produces these and other signs 

 of nicotinate deficiency (Halliday et al., 1957). The endogenous respiration 

 of liver homogenates from treated mice is depressed 70% and lactate oxi- 

 dation is depressed 49%; addition of NAD counteracts these depressions. 

 However, no effect is observed when the analog is added directly to liver 

 slices. The possibility of the formation of a NAD analog was entertained 

 and such an analog was soon isolated following incubation of NAD, 6-ami- 



