Abstract
The presence of a nitrogen atom, charged at physiological pH, has frequently been considered to be a hallmark of P-glycoprotein (PGP) inhibitors, although 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. Propafenone-related amines, anilines, and amides that cover a broad range of pKavalues, as well as an ester, were synthesized and tested for multidrug resistance-reverting activity. The sum of the hydrogen bond acceptor strengths was calculated and correlated with EC50 values for PGP inhibition. For the 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 interaction of the nitrogen atom with PGP therefore is nonional and is determined by the sum of the hydrogen acceptor strengths of the region. The high predictivity of the obtained model is demonstrated in a leave-one-out cross-validation procedure.
Footnotes
-
Send reprint requests to: Dr. Gerhard Ecker, Institute of Pharmaceutical Chemistry, University of Vienna, Althanstraβe 14, A-1090 Wien, Austria. E-mail: ecker{at}speedy.pch.univie.ac.at; or Dr. Peter Chiba, Institute of Medical Chemistry, University of Vienna, Währingerstraβe 14, A-1090 Wien, Austria. E-mail:peter.chiba{at}univie.ac.at
-
This work was supported by grants from the Austrian Science Fund (P11760MOB) and the Austrian National Bank (6899).
- Abbreviations:
- MDR
- multidrug resistance
- PGP
- P-glycoprotein
- Received March 22, 1999.
- Accepted July 15, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
