POLYAMINE-LIKE ACTIONS OF PEPTIDES DERIVED FROM CONANTOKIN-G, AN N-METHYL-D-ASPARTATE (NMDA) ANTAGONIST

Conantokins-T and -G are highly conserved polypeptides derived from Co nus venoms. The N-methyl-D-aspartate (NMDA) antagonist properties of t hese compounds have been attributed to a potent noncompetitive inhibit ion of polyamine responses. Substitution of the highly conserved gamma -carboxyglutamate residues as well as modification of the N and C term ini of conantokin-G abolished the inhibition of polyamine responses at the NMDA receptor complex. However, several of these modified polypep tides closely mimicked the neurochemical profile of polyamines at the NMDA receptor complex. One of these derivatives, Tyr0-conantokin-G, wa s found to be the most potent compound exhibiting polyamine-like actio ns at the NMDA receptor complex described to date, approximately 7-fol d more potent than spermine. Circular dichroism studies demonstrate a significant alpha-helical content in conantokin-G (27% in aqueous medi um). However, this alpha-helicity is not sufficient for the NMDA antag onist action of the parent peptide and is neither necessary nor suffic ient for the polyamine-like behavior of several conantokin-G analogs. The modified conantokin-G derivatives described in this report should be useful probes for examining the role of both polyamines and the pol yamine recognition site in the operation of the NMDA receptor complex.