-Methyl Substitution of Cyclohexylalanine in Dmt-Tic-Cha-Phe Peptides Results in Highly Potent 
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- 作者：Gé ; za Tó ; th ; Eniko Ioja ; Csaba Tö ; mbö ; ly ; Steven Ballet ; Dirk Tourwé ; Antal Pé ; ter ; Tamá ; s Martinek ; Nga N. Chung ; Peter W. Schiller ; Sá ; 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, 
-MeCha (-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 -MeCharesidue. The most promising analog, H-Dmt-Tic-(2S,3S)--MeCha-Phe-OH was a very selective antagonistboth in the mouse vas deferens (MVD) assay (Ke = 0.241 ± 0.05 nM) and in radioligand binding assay (Ki= 0.48 ± 0.05 nM, Ki/Ki = 2800). The epimeric peptide H-Dmt-Tic-(2S,3R)--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 -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.
-MeCha (-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 -MeCharesidue. The most promising analog, H-Dmt-Tic-(2S,3S)--MeCha-Phe-OH was a very selective antagonistboth in the mouse vas deferens (MVD) assay (Ke = 0.241 ± 0.05 nM) and in radioligand binding assay (Ki= 0.48 ± 0.05 nM, Ki/Ki = 2800). The epimeric peptide H-Dmt-Tic-(2S,3R)--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 -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.