β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity
The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca<sup>2+</sup>)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam deriva...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/19/14894 |
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| author | Cristina Martín-Escura M. Ángeles Bonache Jessy A. Medina Alicia Medina-Peris Jorge De Andrés-López Sara González-Rodríguez Sara Kerselaers Gregorio Fernández-Ballester Thomas Voets Antonio Ferrer-Montiel Asia Fernández-Carvajal Rosario González-Muñiz |
| author_facet | Cristina Martín-Escura M. Ángeles Bonache Jessy A. Medina Alicia Medina-Peris Jorge De Andrés-López Sara González-Rodríguez Sara Kerselaers Gregorio Fernández-Ballester Thomas Voets Antonio Ferrer-Montiel Asia Fernández-Carvajal Rosario González-Muñiz |
| author_sort | Cristina Martín-Escura |
| collection | DOAJ |
| description | The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca<sup>2+</sup>)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring <i>C</i>-terminal amides and diversely substituted <i>N</i>′-terminal monobenzyl groups in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca<sup>2+</sup> entry, thereby establishing critical structure–activity relationships. While the substitution of the <i>tert</i>-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the <i>N</i>′-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the transient receptor potential (TRP) ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein. While the four main populated poses are located by the pore zone, a similar location to that described for the N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist cannot be discarded. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin (OXA). |
| first_indexed | 2024-03-10T21:42:49Z |
| format | Article |
| id | doaj.art-7af6439c3de94c3eb426edb908d81259 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:42:49Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7af6439c3de94c3eb426edb908d812592023-11-19T14:32:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124191489410.3390/ijms241914894β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic ActivityCristina Martín-Escura0M. Ángeles Bonache1Jessy A. Medina2Alicia Medina-Peris3Jorge De Andrés-López4Sara González-Rodríguez5Sara Kerselaers6Gregorio Fernández-Ballester7Thomas Voets8Antonio Ferrer-Montiel9Asia Fernández-Carvajal10Rosario González-Muñiz11Instituto de Química Médica (IQM-CSIC), 28006 Madrid, SpainInstituto de Química Médica (IQM-CSIC), 28006 Madrid, SpainInstituto de Química Médica (IQM-CSIC), 28006 Madrid, SpainIDiBE, Universidad Miguel Hernández, 03202 Elche, SpainIDiBE, Universidad Miguel Hernández, 03202 Elche, SpainIDiBE, Universidad Miguel Hernández, 03202 Elche, SpainLaboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, VIB Center for Brain and Disease Research, KU Leuven, Herestraat 49 Box 802, 3000 Leuven, BelgiumIDiBE, Universidad Miguel Hernández, 03202 Elche, SpainLaboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, VIB Center for Brain and Disease Research, KU Leuven, Herestraat 49 Box 802, 3000 Leuven, BelgiumIDiBE, Universidad Miguel Hernández, 03202 Elche, SpainIDiBE, Universidad Miguel Hernández, 03202 Elche, SpainInstituto de Química Médica (IQM-CSIC), 28006 Madrid, SpainThe protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca<sup>2+</sup>)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring <i>C</i>-terminal amides and diversely substituted <i>N</i>′-terminal monobenzyl groups in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca<sup>2+</sup> entry, thereby establishing critical structure–activity relationships. While the substitution of the <i>tert</i>-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the <i>N</i>′-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the transient receptor potential (TRP) ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein. While the four main populated poses are located by the pore zone, a similar location to that described for the N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist cannot be discarded. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin (OXA).https://www.mdpi.com/1422-0067/24/19/14894TRPM8 channelβ-lactamsantagonistsdockingantinociceptive activity |
| spellingShingle | Cristina Martín-Escura M. Ángeles Bonache Jessy A. Medina Alicia Medina-Peris Jorge De Andrés-López Sara González-Rodríguez Sara Kerselaers Gregorio Fernández-Ballester Thomas Voets Antonio Ferrer-Montiel Asia Fernández-Carvajal Rosario González-Muñiz β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity International Journal of Molecular Sciences TRPM8 channel β-lactams antagonists docking antinociceptive activity |
| title | β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity |
| title_full | β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity |
| title_fullStr | β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity |
| title_full_unstemmed | β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity |
| title_short | β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity |
| title_sort | β lactam trpm8 antagonists derived from phe phenylalaninol conjugates structure activity relationships and antiallodynic activity |
| topic | TRPM8 channel β-lactams antagonists docking antinociceptive activity |
| url | https://www.mdpi.com/1422-0067/24/19/14894 |
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