Metabolically programmed polyamine analogue antidiarrheals

The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. While N-1,N-14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providing N-1,N-14-diethyl-(3R),(12R)-dihydroxyhomospermine [(HO)(2)DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)(2)DEHSPM would have a K-i for polyamine transport essentially identical with that of DEHSPM. The experimentally measured K-i and also the observed values of other biological properties of (HO)(2)DEHSPM were in fact identical with those of DEHSPM, including IC50 against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there was no accumulation of the dideethylated metabolite in tissues from mice treated chronically with (HO)(2)DEHSPM, and (HO)(2)DEHSPM was 3-fold less toxic than DEHSPM. Finally, (HO)(2)DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM.