N-terminal guanidinylation of TIPP (Tyr-Tic-Phe-Phe) peptides results in major changes of the opioid activity profile.
Bioorg Med Chem Lett
; 23(18): 5082-5, 2013 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-23932788
ABSTRACT
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.
Palavras-chave
(5α,7α,8ß-(−)-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; bloodbrain 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
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
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Receptores Opioides delta
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Tetra-Hidroisoquinolinas
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Guanidinas
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Canadá
País de publicação:
ENGLAND
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ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
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REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM