The effects of conformational constraints and steric bulk in the amino acid moiety of philanthotoxins on AMPAR antagonism.
Philanthotoxin-343 (PhTX-343), a synthetic analogue of wasp toxin PhTX-433, is a noncompetitive antagonist at ionotropic receptors (e.g., AChR or iGluR). To determine possible effects of variations of the amino acid side chain, a library consisting of seventeen PhTX-343 analogues was prepared. Thus, tyrosine was replaced by either apolar, conformationally constrained, or bulky amino acids, whereas the acyl unit and the polyamine moiety were kept unchanged. Analogues with tertiary amide groups were prepared for the first time. Pentafluorophenyl esters were employed for amide bond formation, establishing general protocols for philanthotoxin solution- and solid-phase synthesis (39-90% and 42-54% overall yields, respectively). The analogues were tested for their ability to antagonize kainate-induced currents of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazoyl)propanoic acid receptors (AMPAR) expressed in Xenopus oocytes from rat brain mRNA. This showed that steric bulk in the amino acid moiety is well tolerated and suggests that binding to AMPAR does not involve the alpha-NHCO group as a donor in hydrogen bonding.
Jørgensen
Malene R
MR
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Olsen
Christian A
CA
Mellor
Ian R
IR
Usherwood
Peter N R
PN
Witt
Matthias
M
Franzyk
Henrik
H
Jaroszewski
Jerzy W
JW
D000818:Animals; D001671:Biochemistry / Q000379:methods; D001921:Brain / Q000502:physiology; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D020128:Inhibitory Concentration 50; D009865:Oocytes / Q000187:drug effects; D010636:Phenols / Q000737:chemistry*; D011073:Polyamines / Q000737:chemistry*; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
D018691:Excitatory Amino Acid Antagonists; D010636:Phenols; D011073:Polyamines; D017470:Receptors, Glutamate; C492973:alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor, human; C074003:philanthotoxin 343