Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives

Detalhes bibliográficos
Autor(a) principal: Serrano, Isa D.
Data de Publicação: 2015
Outros Autores: Ramu, Vasanthakumar G., Pinto, Antónia R. T., Freire, João M., Tavares, Isaura, Heras, Montserrat, Bardaji, Eduard R., Castanho, Miguel A. R. B.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/23431
Resumo: © 2014 Wiley Periodicals, Inc.
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spelling Correlation between membrane translocation and analgesic efficacy in kyotorphin derivativesAnalgesiaBarrierKyotorphinLipophilicityPermeability© 2014 Wiley Periodicals, Inc.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 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.Isa 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/70423/2010WileyRepositório da Universidade de LisboaSerrano, Isa D.Ramu, Vasanthakumar G.Pinto, Antónia R. T.Freire, João M.Tavares, IsauraHeras, MontserratBardaji, Eduard R.Castanho, Miguel A. R. B.2016-04-18T16:12:05Z20152015-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/23431engPeptideScience Volume 104 / Number 10006-352510.1002/bip.22580metadata only accessinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:10:57Zoai:repositorio.ul.pt:10451/23431Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:40:35.039386Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
title Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
spellingShingle Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
Serrano, Isa D.
Analgesia
Barrier
Kyotorphin
Lipophilicity
Permeability
title_short Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
title_full Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
title_fullStr Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
title_full_unstemmed Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
title_sort Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives
author Serrano, Isa D.
author_facet 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.
author_role author
author2 Ramu, Vasanthakumar G.
Pinto, Antónia R. T.
Freire, João M.
Tavares, Isaura
Heras, Montserrat
Bardaji, Eduard R.
Castanho, Miguel A. R. B.
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv 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.
dc.subject.por.fl_str_mv Analgesia
Barrier
Kyotorphin
Lipophilicity
Permeability
topic Analgesia
Barrier
Kyotorphin
Lipophilicity
Permeability
description © 2014 Wiley Periodicals, Inc.
publishDate 2015
dc.date.none.fl_str_mv 2015
2015-01-01T00:00:00Z
2016-04-18T16:12:05Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/23431
url http://hdl.handle.net/10451/23431
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv PeptideScience Volume 104 / Number 1
0006-3525
10.1002/bip.22580
dc.rights.driver.fl_str_mv metadata only access
info:eu-repo/semantics/openAccess
rights_invalid_str_mv metadata only access
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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