Amiloride analogues

Leppik RA, Lazareno S, Mynett A, Birdsall NJM. Characterisation of the allosteric interactions between antagonists and amiloride analogues at the human alpha2A adrenergic receptor. Mol Pharmacol 1998 53 916-925. 

Figure 1 presents the structure of amiloride and that of amiloride analogues that are known to be the most potent inhibitors of epithelium Na+ channels and the Na+/H+ exchanger. Other derivatives of guanidinium that are unrelated to amiloride and that have antihypertensive properties also block the Na+/H+ exchanger (Frelin etal., 1986). 

Inhibition of the enzyme has been shown with pentamidine and other aminoguanidine compounds -specifically aminoguanidine (pimagedine), some amiloride analogues, the alkaloid nazlinin and some derivatives, and metronidazole. Of these, aminoguanidine has mostly been used as a pharmacological tool in the past, but interpretation of findings is complicated by the recent demonstration that it is a potent nitric oxide synthase inhibitor. 

Slaughter, R.S. et al., Inhihition of sodium-calcium exchange in cardiac sarcolemmal membrane vesicles. 1. Mechanism of inhibition by amiloride analogues. Biochemistry, 27, 2403, 1988. 

In nephrogenic diabetes insipidus the kidney s ability to respond to AVP is impaired by different causes, such as drugs (e.g. lithium), chronic disorders (e.g. sickle cell disease, kidney failure) or inherited genetic disorders (X-linked or autosomal NDI). This type of diabetes insipidus can not be treated by exogenous administration of AVP or AVP analogues. Instead, diuretics (hydrochlorothiazide combined or not with amiloride) and NSAI (indomethacin) are administrated to ameliorate polyuria. 

Vigne, P., Frelin, C., Cragoe, EJ., Lazdunski, M. (1984). Structure-activity relationships of amiloride and certain of its analogues in relation to the blockade of the Na 7H+ exchange system. Mol. Pharmacol. 25, 131-136. 

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