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Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
Author(s) -
Serrano Isa D.,
Ramu Vasanthakumar G.,
Pinto Antónia R. T.,
Freire João M.,
Tavares Isaura,
Heras Montserrat,
Bardaji Eduard R.,
Castanho Miguel A. R. B.
Publication year - 2015
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22580
Subject(s) - chemistry , lipophilicity , permeation , dipeptide , in vivo , pharmacology , analgesic , membrane , indole test , ibuprofen , combinatorial chemistry , stereochemistry , biochemistry , amino acid , medicine , microbiology and biotechnology , biology
Amidated kyotorphin ( l ‐Tyr‐ l ‐Arg‐NH 2 ; KTP‐NH 2 ) causes analgesia when systemically administered. The lipophilic ibuprofen‐conjugated derivative of KTP‐NH 2 has improved analgesic efficacy. However, fast degradation by peptidases impacts negatively in the pharmacodynamics of these drugs. In this work, selected derivatives of KTP and KTP‐NH 2 were synthesized to combine lipophilicity and resistance to enzymatic degradation. Eight novel structural modifications were tested for the potential to transverse lipid membranes and to evaluate their efficacy in vivo. The rationale behind the design of the pool of the eight selected molecules consisted in the addition of individual group at the N‐terminus, namely the tert‐butyloxycarbonyl (Boc), γ‐aminobutyric acid (GABA), acetyl, butanoyl, and propanoyl or in the substitution of the tyrosine residue by an indole moiety and in the replacement of the peptidic bond by a urea‐like bond in some cases. All the drugs used in the study are intrinsically fluorescent, which enables the use of spectrofluorimetry to sample the drugs in the permeation assays. The results show that the BOC and indolyl derivatives of KTP‐NH 2 have maximal ability to permeate membranes with concomitant maximal analgesic power. Overall, the results demonstrate that membrane permeation is correlated with analgesic efficacy. However, this is not the only factor accounting for analgesia. KTP‐NH 2 for instance has low passive permeation but is known to have central action. In this case, hypothetical transcytosis over the blood‐brain barrier seems to depend on dipeptide transporters. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 1–10, 2015.