TIPP[.psi.]: a highly potent and stable pseudopeptide .delta. opioid receptor antagonist with extraordinary .delta. selectivity

Pseudopeptide analogues of the delta opioid antagonists H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic-Phe-OH (TIP) containing a reduced peptide bond between the Tic2 and Phe3 residues were synthesized. The two compounds, H-Tyr-Tic psi [CH2NH]Phe-Phe-OH (TIPP [psi]) and H-Tyr-Tic psi-[CH2NH]Phe-OH (TIP [...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1993-10, Vol.36 (21), p.3182-3187
Main Authors: Schiller, Peter W, Weltrowska, Grazyna, Nguyen, Thi M. D, Wilkes, Brian C, Chung, Nga N, Lemieux, Carole
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Biological and medical sciences
Guinea Pigs
Male
Medical sciences
Mice
Molecular Conformation
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Oligopeptides - chemical synthesis
Oligopeptides - metabolism
Oligopeptides - pharmacology
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Receptors, Opioid, delta - antagonists & inhibitors
Receptors, Opioid, delta - metabolism
Tetrahydroisoquinolines
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Summary:Pseudopeptide analogues of the delta opioid antagonists H-Tyr-Tic-Phe-Phe-OH (TIPP) and H-Tyr-Tic-Phe-OH (TIP) containing a reduced peptide bond between the Tic2 and Phe3 residues were synthesized. The two compounds, H-Tyr-Tic psi [CH2NH]Phe-Phe-OH (TIPP [psi]) and H-Tyr-Tic psi-[CH2NH]Phe-OH (TIP [psi]), were tested in mu-, delta-, and kappa-receptor-selective binding assays and in the guinea pig ileum (GPI) and mouse vas deferens (MVD) bioassays. In comparison with their respective parent peptides, both pseudopeptide analogues showed increased delta antagonist potency in the MVD assay, higher delta receptor affinity and further improved delta receptor selectivity. The more potent compound, TIPP [psi], displayed subnanomolar delta receptor affinity and in direct comparisons with other selective delta ligands was shown to have unprecedented delta specificity (Ki mu/Ki delta = 10,500). Furthermore, this compound turned out to be highly stable against enzymatic degradation and, unlike other delta antagonists, showed no mu or kappa antagonist properties. TIPP [psi] is likely to find wide use as a pharmacological tool in opioid research.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00073a020