5-(N,N-Hexamethylene)-amiloride

5-(N,N-hexamethylene)-Amiloride (HMA) is a derivative of amiloride with diverse biological activities.^1,2,3,4,5 It is an allosteric antagonist of adenosine A_2A receptors (K_i = 3.3 ?M).² HMA inhibits the cation-selective ion channel formed by the HIV-1 viral protein Vpu when used at a concentration of 50 ?M, as well as budding of virus-like particles in HeLa cells expressing the HIV-1 proteins Gag and Vpu when used at a concentration of 10 ?M.¹ It also blocks the cation-selective ion channels formed by the hepatitis C virus (HCV) protein p7.³ HMA (40 ?M) induces necrosis in and reduces the viability of MCF-7, MDA-MB-231, T47D, SK-BR-3, Met-1, and NDL breast cancer cells but not cardiomyocytes or uterine, pulmonary, and renal epithelial cells.⁴ HMA protects against post-ischemic contractile dysfunction and reduces coronary effluent creatine phosphokinase activity in a model of ischemia-reperfusion injury using isolated rat right ventricular free walls.⁵

1.Ewart, G.D., Mills, K., Cox, G.B., et al.Amiloride derivatives block ion channel activity and enhancement of virus-like particle budding caused by HIV-1 protein VpuEur. Biophys. J.31(1)26-35(2002) 2.Gao, Z.-G., and Ijzerman, A.P.Allosteric modulation of A2A adenosine receptors by amiloride analogues and sodium ionsBiochem. Pharmacol.60(5)669-679(2000) 3.Premkumar, A., Wilson, L., Ewart, G.D., et al.Cation-selective ion channels formed by p7 of hepatitis C virus are blocked by hexamethylene amilorideFEBS Lett.557(1-3)99-103(2004) 4.Rowson-Hodel, A.R., Berg, A.L., Wald, J.H., et al.Hexamethylene amiloride engages a novel reactive oxygen species- and lysosome-dependent programmed necrotic mechanism to selectively target breast cancer cellsCancer Lett.375(1)62-72(2016) 5.Meng, H.-P., Maddaford, T.G., and Pierce, G.N.Effect of amiloride and selected analogues on postischemic recovery of cardiac contractile functionAm. J. Physiol.264(6 Pt. 2)H1831-H1835(1993)