A chimeric opioid peptide with mixed μ agonist/δ antagonist properties

• Published in: The journal of peptide research 2004-02, Vol.63 (2), p.63-68
• Main Authors: Weltrowska, G., Lemieux, C., Chung, N.N., Schiller, P.W.
• Format: Article
• Language: English
• Subjects: [Dmt1]DALDA; Aldehyde Reductase - chemistry; Aldehyde Reductase - metabolism; Animals; Binding, Competitive; Biological Assay; chimeric opioid peptides; Guinea Pigs; Ileum - drug effects; Mice; mixed μ agonist/δ antagonists; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; opioid peptides; Opioid Peptides - chemical synthesis; Opioid Peptides - chemistry; Opioid Peptides - pharmacology; opioid tolerance and dependence; Rats; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Receptors, sigma - antagonists & inhibitors; Receptors, sigma - metabolism; TICP[Ψ]
• ISSN: 1397-002X; 1399-3011
• DOI: 10.1111/j.1399-3011.2003.00108.x

:  There is evidence to indicate that opioid compounds with mixed μ agonist/δ antagonist properties are analgesics with low propensity to produce tolerance and physical dependence. A chimeric peptide containing the potent and selective μ agonist H‐Dmt‐D‐Arg‐Phe‐Lys‐NH2 ([Dmt1]DALDA) (Dmt = 2′,6′‐dimethyltyrosine) and the potent and selective δ antagonist H‐Tyr‐TicΨ[CH2‐NH]Cha‐Phe‐OH (TICP[Ψ]) (Cha = cyclohexylalanine), connected ‘tail‐to‐tail’ via a short linker, was synthesized using a combination of solid‐phase and solution techniques. The resulting peptide, H‐Dmt→D‐Arg→Phe→Lys‐NH‐CH2‐CH2‐NH‐Phe←Cha[NH‐CH2]ΨTic←Tyr‐H, showed the expected μ agonist/δ antagonist profile in the guinea‐pig ileum and mouse vas deferens assays. Its μ and δ receptor binding affinities were in the low nanomolar range, as determined in rat brain membrane binding assays.