The importance of a nitrogen atom in modulators of multidrug resistance

The presence of a nitrogen atom, charged at physiological pH, has frequentl y been considered to be a hallmark of P-glycoprotein (PGP) inhibitors, alth ough certain steroids, such as progesterone, lack a nitrogen atom and still are active modulators of PGP. The present study was aimed at investigating the role the nitrogen atom plays in the activity of PGP inhibitors. Propaf enone-related amines, anilines, and amides that cover a broad range of pK(a ) values, as well as an ester, were synthesized and tested for multidrug re sistance-reverting activity. The sum of the hydrogen bond acceptor strength s was calculated and correlated with EC50 values for PGP inhibition. For th e complete set of 12 compounds, an excellent correlation between these two parameters was found; this included the ester GP570, which lacks a nitrogen atom but contains the strong hydrogen bond-accepting ester unit. The inter action of the nitrogen atom with PGP therefore is nonional and is determine d by the sum of the hydrogen acceptor strengths of the region. The high pre dictivity of the obtained model is demonstrated in a leave-one-out cross-va lidation procedure.