Gordonsmith R H, Brooke-Taylor S, Smith L L, Cohen G M
Biochem Pharmacol. 1983 Dec 15;32(24):3701-9. doi: 10.1016/0006-2952(83)90138-7.
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.
二胺腐胺通过一个与尸胺、多胺亚精胺和精胺以及除草剂百草枯摄取过程相似的温度和能量依赖性过程在大鼠肺切片中蓄积。使用单胺和二氨基烷烃、氨基酸和胍基化合物进行的构效关系研究表明，为了抑制腐胺在肺中的蓄积，化学物质应至少具有一个但最好有两个含氮阳离子基团。在所研究的一系列α,ω-二氨基烷烃中，抑制潜力随链长增加而增加，在1,7-二氨基庚烷时达到平稳状态。这些观察结果以及腐胺是摄取系统的良好底物（Km为15微摩尔，Vmax为704纳摩尔/克湿重/小时）这一事实表明，有效的抑制剂在其阳离子中心之间至少需要四个亚甲基，并且具有更多亚甲基的二胺可能会折叠以实现这种间隔距离。对于单胺和α,ω-二氨基烷烃，相互作用自由能的变化表明，观察到的抑制潜力随链长增加而增加是由于疏水键合增加，这是向烷基链中添加亚甲基的结果。此外，化合物抑制腐胺摄取的能力似乎与其与腐胺合适位点结合的倾向有关。抑制剂阳离子中心甲基化导致的季铵化对这种离子相互作用的空间位阻，导致可测量的抑制活性完全丧失。同样，在抑制剂中引入阴离子羧基会导致抑制潜力丧失，可能是由于离子排斥作用。抗白血病药物甲基乙二醛双胍腙（MeGAG）及其同系物是所研究的腐胺摄取最有效的抑制剂中的一部分。我们的研究结果表明，腐胺进入肺的摄取系统与针对MeGAG和某些多胺描述的其他摄取系统之间存在相似性。
