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. Guanidinylation of the mixed μ agonist/δ antagonists H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) and H-Dmt-TicΨ[CH2NH]Phe-Phe-NH2 (DIPP-NH2[Ψ]) converted them to mixed μ agonist/δ agonists. 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.
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, QC, Canada.
Grazyna
G
Weltrowska
Thi M-D
TM
Nguyen
Nga N
NN
Chung
Brian C
BC
Wilkes
Peter W
PW
Schiller
D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000737:chemistry*; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D006146:Guanidines; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D044005:Tetrahydroisoquinolines; C082263:tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine
(5α,7α,8β-(−)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; 1,3-diisopropylcarbodiimide; 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; 2′,6′-dimethyltyrosine; 6-chloro-1-hydroxybenzotriazole; BBB; Boc; Cl-HOBt; DAMGO; DIC; DIPP; DIPP-NH(2); DIPP-NH(2)[Ψ]; DSLET; Dmt; ES-MS; GPI; Guan; Guanidinylated opioid peptides; H-Dmt-Tic-Phe-Phe-NH(2); H-Dmt-Tic-Phe-Phe-OH; H-Dmt-TicΨ[CH(2)NH]Phe-Phe-NH(2); H-Tyr-D-Ala-Gly-Phe(NMe)-Gly-ol; H-Tyr-D-Ser-Gly-Phe-Leu-Thr-OH; H-Tyr-Tic-Phe-Phe-OH; H-Tyr-TicΨ[CH(2)NH]Phe-Phe-OH; HBTU; HPLC; MVD; Peptide synthesis; TIPP; TIPP[Ψ]; Tic; U69,593; blood–brain barrier; electrospray mass spectrometry; guanidino; guinea pig ileum; high performance liquid chromatography; mouse vas deferens; tert-butyloxycarbonyl; δ Opioid antagonists; δ Partial opioid agonists; μ Opioid agonist/δ opioid agonists; μ Opioid agonist/δ opioid antagonists