STRUCTURE-ACTIVITY-RELATIONSHIPS OF ANALOGS OF THE WASP TOXIN PHILANTHOTOXIN - NONCOMPETITIVE ANTAGONISTS OF QUISQUALATE RECEPTORS

M. Bruce, R. Bukownik, A. T. Eldefrawi, M. E. Eldefrawi, R. Goodnow, Jr, T. Kallimopoulos, K. Konno, K. Nakanishi, M. Niwa and P. N. R. Usherwood. Structure-activity relationships of analogues of the wasp toxin philanthotoxin: non-competitive antagonists of quisqualate receptors. Toxicon 28, 1333-1346, 1990.-Fifty-two analogues of the wasp toxin, philanthotoxin-433, have been synthesized and tested on a glutamatergic, nerve-muscle preparation from locust leg. Reduction in amplitude of the neurally-evoked muscle twitch was used to construct dose-inhibition relationships from which ic50s were estimated. The most active analogues were characterized by one or more of the following: increased hydrophobicity of aromatic and tyrosyl regions; an increased number of protonated groups in the polyamine region; a guanidinium instead of a spermine terminal amino moiety. The incorporation of a butyl side-group in the polyamine also enhanced potency. These results are explained on the basis of the known non-competitive antagonistic blockage by philanthotoxin-433 of the channel gated by postjunctional glutamate receptors when the channel is open. © 1990.