Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity
Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ nonselective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivat...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/240941 |
| Acceso en línea: | http://hdl.handle.net/10261/240941 |
| Access Level: | acceso abierto |
| Palabra clave: | TRPM8 Antagonists β–lactams Absolute configuration Ca2+ microfluorimetry Patch- Clamp |
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Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist ActivityBonache de Marcos, María ÁngelesLlabrés, Pedro JuanMartín-Escura, CristinaTorre-Martínez, Roberto de laMedina-Peris, AliciaButrón, LauraGómez-Monterrey, IsabelRoa, Ana MaríaFernández-Ballester, GregorioFerrer-Montiel, AntonioFernández-Carvajal, AsiaGonzález-Muñiz, RosarioTRPM8Antagonistsβ–lactamsAbsolute configurationCa2+ microfluorimetryPatch- ClampTransient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ nonselective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivatives, and began to intuit a possible effect of the stereogenic centers on the antagonist activity. To investigate the influence of configuration on the TRPM8 antagonist properties, here we prepare and characterize four possible diastereoisomeric derivatives of 4-benzyl-1-[(3’-phenyl- 2’-dibenzylamino)prop-1’-yl]-4-benzyloxycarbonyl-3-methyl-2-oxoazetidine. In microfluorography assays, all isomers were able to reduce the menthol-induced cell Ca2+ entry to larger or lesser extent. Potency follows the order 3R,4R,2’R > 3S,4S,2’R ≅ 3R,4R,2’S > 3S,4S,2’S, with the most potent diastereoisomer showing a half inhibitory concentration (IC50) in the low nanomolar range, confirmed by Patch-Clamp electrophysiology experiments. All four compounds display high receptor selectivity against other members of the TRP family. Furthermore, in primary cultures of rat dorsal root ganglion (DRG) neurons, the most potent diastereoisomers do not produce any alteration in neuronal excitability, indicating their high specificity for TRPM8 channels. Docking studies positioned these β-lactams at different subsites by the pore zone, suggesting a different mechanism than the known N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist.This research was funded by the Spanish Ministerio de Ciencia y Universidades (MICYU-FEDER, RTI2018-097189-C2-1 to A.F.-M. and A.F.-C., and RTI2018-097189-C2-2 to R.G.M.), Comunidad de Madrid (IND2017/BMD7673 to R.G.M.) and the Spanish National Research Council (CSIC, 201980E030 to R.G.M.).Peer reviewedMultidisciplinary Digital Publishing InstituteComunidad de MadridEuropean CommissionMinisterio de Ciencia, Innovación y Universidades (España)Bonache, María Ángeles [0000-0002-4922-5345]González-Muñiz, Rosario [0000-0001-8833-4328]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202120212021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/240941reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-097189-C2-1info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-097189-C2-2https://doi.org/10.3390/ijms22052370Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2409412026-05-22T06:33:51Z |
| dc.title.none.fl_str_mv |
Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity |
| title |
Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity |
| spellingShingle |
Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity Bonache de Marcos, María Ángeles TRPM8 Antagonists β–lactams Absolute configuration Ca2+ microfluorimetry Patch- Clamp |
| title_short |
Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity |
| title_full |
Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity |
| title_fullStr |
Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity |
| title_full_unstemmed |
Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity |
| title_sort |
Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity |
| dc.creator.none.fl_str_mv |
Bonache de Marcos, María Ángeles Llabrés, Pedro Juan Martín-Escura, Cristina Torre-Martínez, Roberto de la Medina-Peris, Alicia Butrón, Laura Gómez-Monterrey, Isabel Roa, Ana María Fernández-Ballester, Gregorio Ferrer-Montiel, Antonio Fernández-Carvajal, Asia González-Muñiz, Rosario |
| author |
Bonache de Marcos, María Ángeles |
| author_facet |
Bonache de Marcos, María Ángeles Llabrés, Pedro Juan Martín-Escura, Cristina Torre-Martínez, Roberto de la Medina-Peris, Alicia Butrón, Laura Gómez-Monterrey, Isabel Roa, Ana María Fernández-Ballester, Gregorio Ferrer-Montiel, Antonio Fernández-Carvajal, Asia González-Muñiz, Rosario |
| author_role |
author |
| author2 |
Llabrés, Pedro Juan Martín-Escura, Cristina Torre-Martínez, Roberto de la Medina-Peris, Alicia Butrón, Laura Gómez-Monterrey, Isabel Roa, Ana María Fernández-Ballester, Gregorio Ferrer-Montiel, Antonio Fernández-Carvajal, Asia González-Muñiz, Rosario |
| author2_role |
author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Comunidad de Madrid European Commission Ministerio de Ciencia, Innovación y Universidades (España) Bonache, María Ángeles [0000-0002-4922-5345] González-Muñiz, Rosario [0000-0001-8833-4328] Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
TRPM8 Antagonists β–lactams Absolute configuration Ca2+ microfluorimetry Patch- Clamp |
| topic |
TRPM8 Antagonists β–lactams Absolute configuration Ca2+ microfluorimetry Patch- Clamp |
| description |
Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ nonselective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivatives, and began to intuit a possible effect of the stereogenic centers on the antagonist activity. To investigate the influence of configuration on the TRPM8 antagonist properties, here we prepare and characterize four possible diastereoisomeric derivatives of 4-benzyl-1-[(3’-phenyl- 2’-dibenzylamino)prop-1’-yl]-4-benzyloxycarbonyl-3-methyl-2-oxoazetidine. In microfluorography assays, all isomers were able to reduce the menthol-induced cell Ca2+ entry to larger or lesser extent. Potency follows the order 3R,4R,2’R > 3S,4S,2’R ≅ 3R,4R,2’S > 3S,4S,2’S, with the most potent diastereoisomer showing a half inhibitory concentration (IC50) in the low nanomolar range, confirmed by Patch-Clamp electrophysiology experiments. All four compounds display high receptor selectivity against other members of the TRP family. Furthermore, in primary cultures of rat dorsal root ganglion (DRG) neurons, the most potent diastereoisomers do not produce any alteration in neuronal excitability, indicating their high specificity for TRPM8 channels. Docking studies positioned these β-lactams at different subsites by the pore zone, suggesting a different mechanism than the known N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021 2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 |
| format |
article |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/240941 |
| url |
http://hdl.handle.net/10261/240941 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-097189-C2-1 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-097189-C2-2 https://doi.org/10.3390/ijms22052370 Sí |
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info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
| publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
| dc.source.none.fl_str_mv |
reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Consejo Superior de Investigaciones Científicas (CSIC) |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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DIGITAL.CSIC. Repositorio Institucional del CSIC |
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1869412499225313280 |
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15,811543 |