Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives

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,...

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Autores: Serrano, Isa D., Ramu, Vasanthakumar Ganga, Pinto, Antónia R T, Freire, João M., Tavares, Isaura R., Heras i Corominas, Montserrat, Bardají Rodríguez, Eduard, Castanho, Miguel Augusto Rico Botas
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10256/13197
Acceso en línea:http://hdl.handle.net/10256/13197
Access Level:acceso embargado
Palabra clave:Analgèsics
Analgesics
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spelling Correlation between membrane translocation and analgesic efficacy in kyotorphin derivativesSerrano, Isa D.Ramu, Vasanthakumar GangaPinto, Antónia R TFreire, João M.Tavares, Isaura R.Heras i Corominas, MontserratBardají Rodríguez, EduardCastanho, Miguel Augusto Rico BotasAnalgèsicsAnalgesicsAmidated 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 transportersContract 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/70423/2010Wileyinfoinfo2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10256/13197http://hdl.handle.net/10256/13197© Biopolymers - Peptide Science Section, 2015, vol. 104, núm. 1, p. 1-10Articles publicats (D-Q)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/semantics/altIdentifier/doi/10.1002/bip.22580info:eu-repo/semantics/altIdentifier/eissn/1097-0282info:eu-repo/grantAgreement/EC/FP7/230654Tots els drets reservatsinfo:eu-repo/semantics/embargoedAccessoai:recercat.cat:10256/131972026-05-29T05:05:01Z
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.
Analgèsics
Analgesics
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
dc.creator.none.fl_str_mv Serrano, Isa D.
Ramu, Vasanthakumar Ganga
Pinto, Antónia R T
Freire, João M.
Tavares, Isaura R.
Heras i Corominas, Montserrat
Bardají Rodríguez, Eduard
Castanho, Miguel Augusto Rico Botas
author Serrano, Isa D.
author_facet Serrano, Isa D.
Ramu, Vasanthakumar Ganga
Pinto, Antónia R T
Freire, João M.
Tavares, Isaura R.
Heras i Corominas, Montserrat
Bardají Rodríguez, Eduard
Castanho, Miguel Augusto Rico Botas
author_role author
author2 Ramu, Vasanthakumar Ganga
Pinto, Antónia R T
Freire, João M.
Tavares, Isaura R.
Heras i Corominas, Montserrat
Bardají Rodríguez, Eduard
Castanho, Miguel Augusto Rico Botas
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Analgèsics
Analgesics
topic Analgèsics
Analgesics
description 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
publishDate 2015
dc.date.none.fl_str_mv 2015
info
info
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10256/13197
http://hdl.handle.net/10256/13197
url http://hdl.handle.net/10256/13197
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1002/bip.22580
info:eu-repo/semantics/altIdentifier/eissn/1097-0282
info:eu-repo/grantAgreement/EC/FP7/230654
dc.rights.none.fl_str_mv Tots els drets reservats
info:eu-repo/semantics/embargoedAccess
rights_invalid_str_mv Tots els drets reservats
eu_rights_str_mv embargoedAccess
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 © Biopolymers - Peptide Science Section, 2015, vol. 104, núm. 1, p. 1-10
Articles publicats (D-Q)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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