Structural requirements of compounds to inhibit pulmonary diamine accumulation.

The diamine, putrescine, is accumulated into slices of rat lung by a temperature and energy dependent process similar to that responsible for the uptake of cadaverine, the polyamines spermidine and spermine, and the herbicide paraquat. Structure-activity studies using monoamines and diaminoalkanes, amino acids and guanidino compounds, have shown that in order to inhibit the pulmonary accumulation of putrescine, chemicals should possess at least one but preferably two nitrogen-containing cationic groups. In the series of alpha, w-diaminoalkanes studied, the inhibitory potential increased with increasing chain length, reaching a plateau at 1,7-diaminoheptane. These observations together with the fact that putrescine is a good substrate for the uptake system (Km 15 microM, Vmax 704 nmoles/g wet wt/hr) suggest that effective inhibitors require at least four methylene groups between their cationic centres and that diamines with more methylene groups may fold to give this separation. With both the monoamines and the alpha, w-diaminoalkanes, changes in the free energies of interaction suggest that the observed increases in inhibitory potential with increasing chain length are due to increased hydrophobic bonding, which is a consequence of the addition of methylene groups to the alkyl chain. Furthermore, the ability of compounds to inhibit putrescine uptake appears to be related to their propensity to bind with the appropriate site for putrescine. Steric hindrance of this ionic interaction by the quaternisation of the cationic centres of the inhibitors with methyl groups, results in a total loss of measurable inhibitory activity. Also, the introduction of anionic carboxyl groups into inhibitors result in a loss of inhibitory potential, probably due to ionic repulsion. The antileukaemic drug, methylglyoxal-bis-guanylhydrazone (MeGAG), and its congeners, were some of the most potent inhibitors of putrescine uptake studied. Our findings suggest similarities between the uptake system for putrescine into the lung with other uptake systems described for MeGAG and certain polyamines.