| Autor: |
Martín-Escura C; Instituto de Química Médica (IQM-CSIC), 28006 Madrid, Spain.; Alodia Farmacéutica SL, 28108 Alcobendas, Spain., Bonache MÁ; Instituto de Química Médica (IQM-CSIC), 28006 Madrid, Spain., Medina JA; Instituto de Química Médica (IQM-CSIC), 28006 Madrid, Spain., Medina-Peris A; IDiBE, Universidad Miguel Hernández, 03202 Elche, Spain., De Andrés-López J; IDiBE, Universidad Miguel Hernández, 03202 Elche, Spain., González-Rodríguez S; IDiBE, Universidad Miguel Hernández, 03202 Elche, Spain.; Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Julián Clavería 6, 33006 Oviedo, Spain., Kerselaers S; Laboratory 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, Belgium., Fernández-Ballester G; IDiBE, Universidad Miguel Hernández, 03202 Elche, Spain., Voets T; Laboratory 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, Belgium., Ferrer-Montiel A; IDiBE, Universidad Miguel Hernández, 03202 Elche, Spain., Fernández-Carvajal A; IDiBE, Universidad Miguel Hernández, 03202 Elche, Spain., González-Muñiz R; Instituto de Química Médica (IQM-CSIC), 28006 Madrid, Spain. |
| Abstrakt: |
The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca 2+ )-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 C -terminal amides and diversely substituted N '-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 2+ entry, thereby establishing critical structure-activity relationships. While the substitution of the tert -butyl ester by isobutyl amide moieties improved the antagonist activity, none of the N '-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). |
