Structure-activity relationships of analogues of the wasp toxin philanthotoxin: non-competitive antagonists of quisqualate receptors.
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.
Bruce
M
M
Department of Zoology, School of Biological Sciences, University of Nottingham, U.K.
Bukownik
R
R
Eldefrawi
A T
AT
Eldefrawi
M E
ME
Goodnow
R
R
Kallimopoulos
T
T
Konno
K
K
Nakanishi
K
K
Niwa
M
M
Usherwood
P N
PN
D000818:Animals; D005260:Female; D006110:Grasshoppers; D015394:Molecular Structure; D009132:Muscles / Q000187:drug effects; D010069:Oxadiazoles / Q000378:metabolism; D011073:Polyamines; D018091:Receptors, AMPA; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014862:Wasp Venoms / Q000737:chemistry / Q000494:pharmacology*; D014863:Wasps
D010069:Oxadiazoles; D011073:Polyamines; D018091:Receptors, AMPA; D017981:Receptors, Neurotransmitter; D014862:Wasp Venoms; C034092:delta-philanthotoxin