The effects of alanine-substituted conantokin-G and ifenprodil on the human spermine-activated N-methyl-d-aspartate receptor

Abstract: We evaluated the effects of Ala-7-conantokin-G (Con-GA7) and ifenprodil on the modulation by spermine of [3H]MK801 binding to human cortical membranes. Human cortical tissue was obtained at autopsy and stored at −80 °C until assay. Both Con-GA7 and ifenprodil inhibited [3H]MK801 binding, but spermine affected these inhibitions differently. Con-GA7 IC50 changed little with spermine concentration, indicative of a non-competitive interaction, whereas the rightward shift in ifenprodil IC50 with increasing spermine concentration suggested partial competition. When the two agents were tested against the biphasic activation of [3H]MK801 binding by spermine, they again differed in their effects. In the activation phase Con-GA7 was a non-competitive inhibitor of spermine activation, and may even enhance the spermine EC50, while the ifenprodil data indicated a partially competitive interaction. Both agents were non-competitive in the inhibitory phase. Overall, the data suggest that Con-GA7 and ifenprodil interact differently with the polyamine modulation of the glutamate–N-methyl-d-aspartate receptor. [Copyright &y& Elsevier]