INHIBITORS OF HISTAMINE-METABOLISM INVITRO AND INVIVO - CORRELATIONS WITH ANTITRYPANOSOMAL ACTIVITY

The effects of antimalarial and antitrypanosomal drugs on the activity of histamine N-methyl transferase and diamine oxidase in vitro, as well as diamine oxidation and histamine levels in vivo, were examined. Diamidine antitrypanosomal drugs which interfere with polyamine metabolism were found to be potent inhibitors both in vitro and in vivo. Antrycide (quinapyramine) and isometamidium were the best inhibitors of both enzymes. Ki values for histamine N-methyl transferase were 3 .times. 10-8 M for both compounds, and the inhibition was competitive for histamine. Antrycide and isometamidium were both noncompetitive inhibitors of diamine oxidase, having Ki values of 6 .times. 10-9 M, and 3 .times. 10-9 M, respectively. Isometamidium elevated histamine levels in rat kidney 2-fold and produced a long-term inhibition of putrescine oxidation in vivo. Among the compounds examined, only known active antitrypanosomal agents inhibited both histamine N-methyl transferase and diamine oxidase in vitro as well as putrescine oxidation in vivo. Apparently, the enzymes acting on histamine and putrescine as substrates can be used to select compounds which interfere with polyamine metabolism and persistence of such compounds in vivo, as indicated by inhibition of putrescine oxidation, correlates with favorable chemotherapeutic properties as antitrypanosomal agents.