alpha-Cl-alpha-Br-phosphonoacetic acid is a potent and selective inhibitor of Na+/Pi cotransport across renal cortical brush border membrane.
We found that alpha-Cl-alpha-Br-phosphonoacetate (ClBrPAA) is a competitive, solute-specific inhibitor of Na+/Pi cotransport across renal cortical brush border membrane. Inhibition by ClBrPAA (Ki = 62 microM) is more than three times more effective than inhibition by phosphonoformate (PFA), the most potent Na+/Pi cotransport inhibitor known to date, and 26 times more effective than the parent compound, phosphonoacetate (PAA). These observations indicate that substitution of bromine and chlorine atoms at the alpha-carbon of PAA greatly enhances its efficacy as a competitive inhibitor of Na+/Pi cotransport. As ClBrPAA is much less inhibitory than PAA and PFA towards viral DNA polymerases and did not inhibit human alpha-DNA polymerase (ref. 10), the results also demonstrate that Na+/Pi cotransport inhibition can be dissociated from inhibition of DNA polymerases by phosphonocarboxylate compounds.
Hoppe
A
A
Nephrology Research Unit, Mayo Clinic and Foundation, Rochester, MN 55905.
McKenna
C E
CE
Harutunian
V
V
Levy
J N
JN
Dousa
T P
TP
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects / Q000648:ultrastructure*; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D011392:Proline / Q000378:metabolism; D051381:Rats; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters
D002352:Carrier Proteins; D009943:Organophosphorus Compounds; D010710:Phosphates; D050608:Sodium-Phosphate Cotransporter Proteins; D027981:Symporters; C056370:alpha-chloro-alpha-bromophosphonoacetic acid; D011392:Proline; D005947:Glucose; D010746:Phosphonoacetic Acid