Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
dc.contributor.author
dc.date.accessioned
2016-11-22T11:58:14Z
dc.date.available
2016-11-22T11:58:14Z
dc.date.issued
2015-01-01
dc.identifier.uri
dc.description.abstract
Amidated kyotorphin (L-Tyr-L-Arg-NH2; KTP-NH2) causes analgesia when systemically administered. The lipophilic ibuprofen-conjugated derivative of KTP-NH2 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-NH2 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-NH2 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-NH2 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
dc.description.sponsorship
Contract grant sponsor: Fundaçao para a Ciéncia e Tecnologia – Minist erio da Ciéncia, Tecnologia e Ensino Superior (FCT-MCTES, Portugal), EC-FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP)
Contract grant number: 230654, PTDC/QUI/69937/2006, PTDC/QUI-BIQ/112929/2009
Contract grant sponsor: FP7-PEOPLE IRSES (International Research Staff Exchange Scheme) project MEMPEPACROSS
Contract grant sponsor: FCT-MCTES
Contract grant number: SFRH/BPD/37998/2007, PTDC/QUIBIQ/114774/2009, SFRH/BD/70423/2010
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
Wiley
dc.relation.isformatof
Reproducció digital del document publicat a: http://dx.doi.org/10.1002/bip.22580
dc.relation.ispartof
© Biopolymers - Peptide Science Section, 2015, vol. 104, núm. 1, p. 1-10
dc.relation.ispartofseries
Articles publicats (D-Q)
dc.rights
Tots els drets reservats
dc.subject
dc.title
Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/embargoedAccess
dc.embargo.terms
Cap
dc.date.embargoEndDate
info:eu-repo/date/embargoEnd/2026-01-01
dc.relation.projectID
info:eu-repo/grantAgreement/EC/FP7/230654/EU/Selected peptides as drug candidates directed to pain and neurodegeneration/PEP2BRAIN
dc.type.version
info:eu-repo/semantics/publishedVersion
dc.identifier.doi
dc.identifier.idgrec
023785
dc.relation.FundingProgramme
dc.relation.ProjectAcronym
dc.identifier.eissn
1097-0282