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Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives

2015Journal article Restricted access
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dc.contributor.authorSerrano, Isa D.
dc.contributor.authorRamu, Vasanthakumar G.
dc.contributor.authorPinto, Antónia R. T.
dc.contributor.authorFreire, João M.
dc.contributor.authorTavares, Isaura
dc.contributor.authorHeras, Montserrat
dc.contributor.authorBardaji, Eduard R.
dc.contributor.authorCastanho, Miguel A. R. B.
dc.date.accessioned2016-04-18T16:12:05Z
dc.date.available2016-04-18T16:12:05Z
dc.date.issued2015
dc.description© 2014 Wiley Periodicals, Inc.pt_PT
dc.description.abstractAmidated 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 atthe N-terminus, namely the tert-butyloxycarbonyl (Boc), -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.pt_PT
dc.description.sponsorshipIsa D. Serrano and Vasanthakumar G. Ramu contributed equally to this work Contract grant sponsor: Fundação para a Ciência e Tecnologia–Ministério da Ciência, 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/70423/2010pt_PT
dc.identifier.citationPeptideScience Volume 104 / Number 1pt_PT
dc.identifier.doi10.1002/bip.22580pt_PT
dc.identifier.issn0006-3525
dc.identifier.urihttp://hdl.handle.net/10451/23431
dc.language.isoengpt_PT
dc.publisherWileypt_PT
dc.relationThe role of lipid membranes in Dengue virus cell infection
dc.relationGENOMIC AND EPI-GENOMIC EFFECTS OF THERMAL STRESS IN VITIS VINIFERA
dc.relationMembrane fusion mechanism of Influenza Hemagglutinin: a simulation and biophysical approach.
dc.relation.publisherversionhttp://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1097-0282pt_PT
dc.subjectAnalgesiapt_PT
dc.subjectBarrierpt_PT
dc.subjectKyotorphinpt_PT
dc.subjectLipophilicitypt_PT
dc.subjectPermeabilitypt_PT
dc.titleCorrelation between membrane translocation and analgesic efficacy in kyotorphin derivativespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleThe role of lipid membranes in Dengue virus cell infection
oaire.awardTitleGENOMIC AND EPI-GENOMIC EFFECTS OF THERMAL STRESS IN VITIS VINIFERA
oaire.awardTitleMembrane fusion mechanism of Influenza Hemagglutinin: a simulation and biophysical approach.
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI%2F69937%2F2006/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI-BIQ%2F112929%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F37998%2F2007/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI-BIQ%2F114774%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F70423%2F2010/PT
oaire.citation.titleBiopolymers (Peptide Science)pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStreamSFRH
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsclosedAccesspt_PT
rcaap.typearticlept_PT
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