Side chain methyl substitution in the δ-opioid receptor antagonist TIPP has an important effect on the activity profile

被引:50
作者
Tourwé, D
Mannekens, E
Diem, TNT
Verheyden, P
Jaspers, H
Tóth, G
Péter, A
Kertész, I
Török, G
Chung, NN
Schiller, PW
机构
[1] Free Univ Brussels, B-1050 Brussels, Belgium
[2] Hungarian Acad Sci, Biol Res Ctr, Isotope Lab, H-6701 Szeged, Hungary
[3] Attila Jozsef Univ, Dept Inorgan & Analyt Chem, H-6701 Szeged, Hungary
[4] Clin Res Inst Montreal, Lab Chem Biol & Peptide Res, Montreal, PQ H2W 1R7, Canada
关键词
D O I
10.1021/jm981011u
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The delta-opioid antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP-OH) or its C-terminal amide analogue was systematically modified topologically by substitution of each amino acid residue by all stereoisomers of the corresponding beta-methyl amino acid. The potency and selectivity (delta- vs mu- and kappa-opioid receptor) were evaluated by radioreceptor binding assays. Agonist or antagonist potency were assayed in the mouse vas deferens and in the guinea pig ileum. In the TIPP analogues containing L-beta-methyl amino acids the influence on delta-receptor affinity and on delta-antagonist potency is limited, the [(2S,3R)-beta-MePhe(3)]TIPP-OH analogue being among the most potent delta-antagonists reported. In the D-beta-methyl amino acid series, the [D-beta-MeTic(2)] analogues are delta-selective antagonists whereas [D-Tic(2)]TIPP-NH2 is a delta-agonist. NMR studies did not indicate any influence of the beta-methyl substituent on the conformation of the Tic residue. The [(2R,3S)-beta-MePhe(3)]TIPP-NH2 is a potent delta-agonist, its C-terminal carboxylic acid analogue being more delta-selective but displaying partial agonism in both the delta- and mu-bioassay. These results constitute further examples of a profound influence of beta-methyl substitution on the potency, selectivity, and signal transduction properties of a peptide.
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页码:5167 / 5176
页数:10
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