-Methyl Substitution of Cyclohexylalanine in Dmt-Tic-Cha-Phe Peptides Results in Highly Potent p://pubs.

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• 作者：Gé ; za Tó ; th ; Eniko Ioja ; Csaba Tö ; mbö ; ly ; Steven Ballet ; Dirk Tourwé ; Antal Pé ; ter ; Tam&aacute ; s Martinek ; Nga N. Chung ; Peter W. Schiller ; S&aacute ; ndor Benyhe ; Anna B
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：January 25, 2007
• 年：2007
• 卷：50
• 期：2
• 页码：328 - 333
• 全文大小：65K
• 年卷期：v.50,no.2(January 25, 2007)
• ISSN：1520-4804

文摘

The opioid peptide TIPP (H-Tyr-Tic-Phe-Phe-OH, Tic:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) wassubstituted with Dmt (2',6'-dimethyltyrosine) and a new unnatural amino acid, beta2.gif" BORDER=0 ALIGN="middle">-MeCha (beta2.gif" BORDER=0 ALIGN="middle">-methyl-cyclohexylalanine). This double substitution led to a new series of opioid peptides displaying subnanomolar antagonist activity and agonist or antagonist properties depending on the configuration of the beta2.gif" BORDER=0 ALIGN="middle">-MeCharesidue. The most promising analog, H-Dmt-Tic-(2S,3S)-beta2.gif" BORDER=0 ALIGN="middle">-MeCha-Phe-OH was a very selective antagonistboth in the mouse vas deferens (MVD) assay (K_e = 0.241 ± 0.05 nM) and in radioligand binding assay (K_i= 0.48 ± 0.05 nM, K_i/K_i = 2800). The epimeric peptide H-Dmt-Tic-(2S,3R)-beta2.gif" BORDER=0 ALIGN="middle">-MeCha-Phe-OH and thecorresponding peptide amide turned out to be mixed partial agonist/ antagonists in the guinea pig ileumand MVD assays. Our results constitute further examples of the influence of Dmt and beta2.gif" BORDER=0 ALIGN="middle">-methyl substitutionas well as C-terminal amidation on the potency, selectivity, and signal transduction properties of TIPPrelated peptides. Some of these compounds represent valuable pharmacological tools for opioid research.