Novel TIPP (Tyr-Tic-Phe-Phe) Analogues with Unexpected Opioid Actvity Profiles

摘要

The TIPP peptides H-Tyr-Tic-Phe-Phe-OH (TIPP, Tic = l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), H-Dmt-Tic-Phe-Phe-OH (DIPP, Dmt = 2',6'-dimethyltyrosine) and H-Tyr-Ticψ[CH2NH]Phe-Phe-OH (TIPP[ψ]) are highly selective 8 opioid antagonists, whereas the TIPP-derived tetrapeptide amides H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) and H-Dmt-Ticψ[eH2NH]Phe-Phe-NH2 (DIPP-NH2[ψ]) act as agonists at the μ opioid receptor and as antagonists at the δ opioid receptor [1]. Such mixed μ agonist/8 antagonists have therapeutic potential as analgesics with low propensity to induce analgesic tolerance and dependence [2]. In an effort to improve the ability of TIPP peptides to cross the blood-brain barrier, we prepared N-terminally guanidinylated analogues (Gu-peptides). Compounds were prepared by solid-phase and solution techniques and were tested in opioid receptor binding assays and in the functional guinea pig ileum (GPI) and mouse vas deferens (MVD) assays.