The effects of conformational constraints and steric bulk in the amino acid moiety of philanthotoxins on AMPAR antagonism
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The effects of conformational constraints and steric bulk in the amino acid moiety of philanthotoxins on AMPAR antagonism. / Jørgensen, Malene; Olsen, Christian A; Mellor, Ian R; Usherwood, Peter N R; Witt, Matthias; Franzyk, Henrik; Jaroszewski, Jerzy W.
In: Journal of Medicinal Chemistry, Vol. 48, No. 1, 2005, p. 56-70.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The effects of conformational constraints and steric bulk in the amino acid moiety of philanthotoxins on AMPAR antagonism
AU - Jørgensen, Malene
AU - Olsen, Christian A
AU - Mellor, Ian R
AU - Usherwood, Peter N R
AU - Witt, Matthias
AU - Franzyk, Henrik
AU - Jaroszewski, Jerzy W
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
KW - Animals
KW - Biochemistry
KW - Brain
KW - Cells, Cultured
KW - Drug Evaluation, Preclinical
KW - Excitatory Amino Acid Antagonists
KW - Female
KW - Inhibitory Concentration 50
KW - Oocytes
KW - Phenols
KW - Polyamines
KW - Rats
KW - Receptors, Glutamate
KW - Structure-Activity Relationship
U2 - 10.1021/jm049906w
DO - 10.1021/jm049906w
M3 - Journal article
C2 - 15634001
VL - 48
SP - 56
EP - 70
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 1
ER -
ID: 42364299