β-Methyl Substitution of Cyclohexylalanine in Dmt-Tic-Cha-Phe Peptides Results in Highly Potent δ Opioid Antagonists

The opioid peptide TIPP (H-Tyr-Tic-Phe-Phe-OH, Tic:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) was substituted with Dmt (2‘,6‘-dimethyltyrosine) and a new unnatural amino acid, β-MeCha (β-methyl-cyclohexylalanine). This double substitution led to a new series of opioid peptides displaying subn...

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Bibliographic Details
Published in:	Journal of medicinal chemistry 2007-01, Vol.50 (2), p.328-333
Main Authors:	Tóth, Géza, Ioja, Enikő, Tömböly, Csaba, Ballet, Steven, Tourwé, Dirk, Péter, Antal, Martinek, Tamás, Chung, Nga N., Schiller, Peter W., Benyhe, Sándor, Borsodi, Anna
Format:	Article
Language:	eng
Subjects:	Animals Binding, Competitive Biological and medical sciences Brain - metabolism Guinea Pigs Ileum - drug effects Ileum - physiology In Vitro Techniques Male Medical sciences Mice Muscle Contraction - drug effects Muscle, Smooth - drug effects Muscle, Smooth - physiology Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Oligopeptides - chemical synthesis Oligopeptides - chemistry Oligopeptides - pharmacology Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Phenylalanine - analogs & derivatives Phenylalanine - chemistry Radioligand Assay Rats Rats, Wistar Receptors, Opioid, delta - antagonists & inhibitors Receptors, Opioid, mu - agonists Stereoisomerism Structure-Activity Relationship Vas Deferens - drug effects Vas Deferens - physiology
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Summary:	The opioid peptide TIPP (H-Tyr-Tic-Phe-Phe-OH, Tic:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) was substituted with Dmt (2‘,6‘-dimethyltyrosine) and a new unnatural amino acid, β-MeCha (β-methyl-cyclohexylalanine). This double substitution led to a new series of opioid peptides displaying subnanomolar δ antagonist activity and μ agonist or antagonist properties depending on the configuration of the β-MeCha residue. The most promising analog, H-Dmt-Tic-(2S,3S)-β-MeCha-Phe-OH was a very selective δ antagonist both in the mouse vas deferens (MVD) assay (K e = 0.241 ± 0.05 nM) and in radioligand binding assay (K i δ = 0.48 ± 0.05 nM, K i μ/K i δ = 2800). The epimeric peptide H-Dmt-Tic-(2S,3R)-β-MeCha-Phe-OH and the corresponding peptide amide turned out to be mixed partial μ agonist/δ antagonists in the guinea pig ileum and MVD assays. Our results constitute further examples of the influence of Dmt and β-methyl substitution as well as C-terminal amidation on the potency, selectivity, and signal transduction properties of TIPP related peptides. Some of these compounds represent valuable pharmacological tools for opioid research.
ISSN:	0022-2623 1520-4804