Bioorganic & medicinal chemistry letters
-
Bioorg. Med. Chem. Lett. · Sep 2013
N-terminal guanidinylation of TIPP (Tyr-Tic-Phe-Phe) peptides results in major changes of the opioid activity profile.
Derivatives of peptides of the TIPP (Tyr-Tic-Phe-Phe; Tic=1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) family containing a guanidino (Guan) function in place of the N-terminal amino group were synthesized in an effort to improve their blood-brain barrier permeability. Unexpectedly, N-terminal amidination significantly altered the in vitro opioid activity profiles. Guan-analogues of TIPP-related δ opioid antagonists showed δ partial agonist or mixed δ partial agonist/μ partial agonist activity. ⋯ A docking study revealed distinct positioning of DIPP-NH2 and Guan-DIPP-NH2 in the δ receptor binding site. Lys(3)-analogues of DIPP-NH2 and DIPP-NH2[Ψ] (guanidinylated or non-guanidinylated) turned out to be mixed μ/κ agonists with δ antagonist-, δ partial agonist- or δ full agonist activity. Compounds with some of the observed mixed opioid activity profiles have therapeutic potential as analgesics with reduced side effects or for treatment of cocaine addiction.
-
Bioorg. Med. Chem. Lett. · Sep 2013
De novo design and synthesis of a μ-conotoxin KIIIA peptidomimetic.
μ-Conotoxin KIIIA blocks voltage-gated sodium channels and displays potent analgesic activity in mice models for pain. Structure-activity studies with KIIIA have shown that residues important for sodium channel activity are presented on an α-helix. Herein, we report the de novo design and synthesis of a three-residue (Lys7, Trp8, His12) peptidomimetic based on a novel diketopiperazine (DKP) carboxamide scaffold.