Phenylalanine-derived β-lactam TRPM8 antagonists: revisiting configuration and new benzoyl derivatives
Aim: To expand the understanding of the structure-activity relationship within a family of amino acid-derived β-lactam TRPM8 (transient receptor potential melastatin channel, subtype 8) antagonists, this work investigated both the configuration-dependence of potency and selectivity, and explored str...
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Open Exploration
2025-01-01
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| Series: | Exploration of Drug Science |
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| Online Access: | https://www.explorationpub.com/uploads/Article/A100882/100882.pdf |
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| author | Cristina Martín-Escura Maria Angeles Bonache Alicia Medina-Peris Thomas Voets Antonio Ferrer-Montiel Asia Fernández-Carvajal Rosario González-Muñiz |
| author_facet | Cristina Martín-Escura Maria Angeles Bonache Alicia Medina-Peris Thomas Voets Antonio Ferrer-Montiel Asia Fernández-Carvajal Rosario González-Muñiz |
| author_sort | Cristina Martín-Escura |
| collection | DOAJ |
| description | Aim: To expand the understanding of the structure-activity relationship within a family of amino acid-derived β-lactam TRPM8 (transient receptor potential melastatin channel, subtype 8) antagonists, this work investigated both the configuration-dependence of potency and selectivity, and explored strategies for increasing total polar surface area (TPSA). Methods: Diastereoisomeric compounds derived from H-Phe-OtBu, and analogues incorporating differently substituted benzoyl groups, were synthesized by stereoselective solution pathways. Ca2+ microfluorometry assays were used for TRPM8 antagonist activity assessment, and then confirmed through electrophysiology (patch-clamp assay). The pharmacological activity in vivo was studied on a mice model of oxaliplatin-induced peripheral neuropathy. Results: For OtBu derivatives, a 3S,4S-configuration was preferred, while compounds with 2'R chiral centers show higher selectivity for TRPM8 versus transient receptor potential vanilloid, subtype 1 (TRPV1) than their 2'S-counterparts. N-terminal benzoyl derivatives, which increased TPSA values, resulted in equipotent compounds as previous prototypes, but also showed activity in other pain-related targets [TRPV1 and cannabinoid receptor, subtype 2 (CB2R)]. A selected N-benzoyl derivative displays antinociceptive activity in vivo. Conclusions: The potency and selectivity of these β-lactam TRPM8 antagonists developed from amino acid derivatives depend not only on the configuration but also on the substituents at the 4-carboxy and at the N-benzoyl groups. Dual and multitarget compounds were discovered within this family of TRPM8 antagonists. |
| format | Article |
| id | doaj-art-c2975617761f405c8b271d1a0f0532e9 |
| institution | Kabale University |
| issn | 2836-7677 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Open Exploration |
| record_format | Article |
| series | Exploration of Drug Science |
| spelling | doaj-art-c2975617761f405c8b271d1a0f0532e92025-02-08T03:05:27ZengOpen ExplorationExploration of Drug Science2836-76772025-01-01310088210.37349/eds.2025.100882Phenylalanine-derived β-lactam TRPM8 antagonists: revisiting configuration and new benzoyl derivativesCristina Martín-Escura0https://orcid.org/0000-0002-8760-5621Maria Angeles Bonache1https://orcid.org/0000-0002-4922-5345Alicia Medina-Peris2https://orcid.org/0000-0002-8035-0179Thomas Voets3https://orcid.org/0000-0001-5526-5821Antonio Ferrer-Montiel4https://orcid.org/0000-0002-2973-6607Asia Fernández-Carvajal5https://orcid.org/0000-0003-2741-1427Rosario González-Muñiz6https://orcid.org/0000-0001-8833-4328Departamento de Biomiméticos para el descubrimiento de fármacos, Instituto de Química Médica (IQM-CSIC), 28006 Madrid, Spain; Alodia Farmacéutica SL, 28108 Alcobendas, SpainDepartamento de Biomiméticos para el descubrimiento de fármacos, Instituto de Química Médica (IQM-CSIC), 28006 Madrid, SpainInstituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03202 Elche, SpainVIB Center for Brain and Disease Research, KU Leuven, 3000 Leuven, BelgiumInstituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03202 Elche, SpainInstituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03202 Elche, SpainDepartamento de Biomiméticos para el descubrimiento de fármacos, Instituto de Química Médica (IQM-CSIC), 28006 Madrid, SpainAim: To expand the understanding of the structure-activity relationship within a family of amino acid-derived β-lactam TRPM8 (transient receptor potential melastatin channel, subtype 8) antagonists, this work investigated both the configuration-dependence of potency and selectivity, and explored strategies for increasing total polar surface area (TPSA). Methods: Diastereoisomeric compounds derived from H-Phe-OtBu, and analogues incorporating differently substituted benzoyl groups, were synthesized by stereoselective solution pathways. Ca2+ microfluorometry assays were used for TRPM8 antagonist activity assessment, and then confirmed through electrophysiology (patch-clamp assay). The pharmacological activity in vivo was studied on a mice model of oxaliplatin-induced peripheral neuropathy. Results: For OtBu derivatives, a 3S,4S-configuration was preferred, while compounds with 2'R chiral centers show higher selectivity for TRPM8 versus transient receptor potential vanilloid, subtype 1 (TRPV1) than their 2'S-counterparts. N-terminal benzoyl derivatives, which increased TPSA values, resulted in equipotent compounds as previous prototypes, but also showed activity in other pain-related targets [TRPV1 and cannabinoid receptor, subtype 2 (CB2R)]. A selected N-benzoyl derivative displays antinociceptive activity in vivo. Conclusions: The potency and selectivity of these β-lactam TRPM8 antagonists developed from amino acid derivatives depend not only on the configuration but also on the substituents at the 4-carboxy and at the N-benzoyl groups. Dual and multitarget compounds were discovered within this family of TRPM8 antagonists.https://www.explorationpub.com/uploads/Article/A100882/100882.pdftrpm8 channelsβ-lactamspeptidomimeticsantagonistsconfigurationbenzoyl derivatives |
| spellingShingle | Cristina Martín-Escura Maria Angeles Bonache Alicia Medina-Peris Thomas Voets Antonio Ferrer-Montiel Asia Fernández-Carvajal Rosario González-Muñiz Phenylalanine-derived β-lactam TRPM8 antagonists: revisiting configuration and new benzoyl derivatives Exploration of Drug Science trpm8 channels β-lactams peptidomimetics antagonists configuration benzoyl derivatives |
| title | Phenylalanine-derived β-lactam TRPM8 antagonists: revisiting configuration and new benzoyl derivatives |
| title_full | Phenylalanine-derived β-lactam TRPM8 antagonists: revisiting configuration and new benzoyl derivatives |
| title_fullStr | Phenylalanine-derived β-lactam TRPM8 antagonists: revisiting configuration and new benzoyl derivatives |
| title_full_unstemmed | Phenylalanine-derived β-lactam TRPM8 antagonists: revisiting configuration and new benzoyl derivatives |
| title_short | Phenylalanine-derived β-lactam TRPM8 antagonists: revisiting configuration and new benzoyl derivatives |
| title_sort | phenylalanine derived β lactam trpm8 antagonists revisiting configuration and new benzoyl derivatives |
| topic | trpm8 channels β-lactams peptidomimetics antagonists configuration benzoyl derivatives |
| url | https://www.explorationpub.com/uploads/Article/A100882/100882.pdf |
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