The phosphonate compounds 3-aminopropylphosphonate (APP) and 2-amino-4-phosphonobutyrate were assessed as analogues of gamma-aminobutyrate (GABA) and L-glutamate, respectively, in a range of systems involved in the neurotransmitter roles of GABA and L-glutamate in mammalian brain. These systems included sites for post-synaptic binding and high-affinity uptake and a number of enzymes. APP was shown to inhibit the binding of GABA to its post-synaptic receptor, having an IC50 value of 7.08 mM and, at 2.0 mM, to have no effect on the high-affinity uptake of GABA. APP inhibited GABA:2-oxoglutarate aminotransferase (E.C.22.214.171.124) by 58% at 25 mM and was a substrate for this enzyme (17% of the rate obtained with 25 mM-GABA). APB (at 1.0 mM) was shown not to interact with the high affinity uptake system for L-glutamate and had no effect on L-glutamate:oxaloacetate aminotransferase (E.C.126.96.36.199) at 25.0 mM. At 10.0 mM APB inhibited L-alanine:2-oxoglutarate aminotransferase (E.C.188.8.131.52) by 11% and L-glutamate decarboxylase (E.C.184.108.40.206) by 29% but had no effect on L-glutamine synthetase (E.C.220.127.116.11). APB inhibited L-glutamate dehydrogenase (E.C.18.104.22.168) and kinetic analysis showed that three inhibition mechanisms were possible all of which involved binding by APB to both the L-glutamate and NAD+ binding sites. True Ki values were determined and were between 0.1 and 4.0 mM.
|Date of Award||1980|