| Autor: |
Iraci N; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166 Messina, Italy., Ostacolo C; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy., Medina-Peris A; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Avenida de la Universidad, 03202 Elche, Spain., Ciaglia T; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy., Novoselov AM; Department of Chemistry, Lomonosov Moscow State University, 1/3 Leninsky Gory, 119991 Moscow, Russia., Altieri A; Department of Chemistry, Lomonosov Moscow State University, 1/3 Leninsky Gory, 119991 Moscow, Russia.; EDASA Scientific srls, Via Stingi 37, 66050 San Salvo, Italy., Cabañero D; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Avenida de la Universidad, 03202 Elche, Spain., Fernandez-Carvajal A; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Avenida de la Universidad, 03202 Elche, Spain., Campiglia P; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy., Gomez-Monterrey I; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy., Bertamino A; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy., Kurkin AV; Department of Chemistry, Lomonosov Moscow State University, 1/3 Leninsky Gory, 119991 Moscow, Russia. |
| Abstrakt: |
Transient receptor potential melastatin type 8 (TRPM8) is a target for the treatment of different physio-pathological processes. While TRPM8 antagonists are reported as potential drugs for pain, cancer, and inflammation, to date only a limited number of chemotypes have been investigated and thus a limited number of compounds have reached clinical trials. Hence there is high value in searching for new TRPM8 antagonistic to broaden clues to structure-activity relationships, improve pharmacological properties and explore underlying molecular mechanisms. To address this, the EDASA Scientific in-house molecular library has been screened in silico, leading to identifying twenty-one potentially antagonist compounds of TRPM8. Calcium fluorometric assays were used to validate the in-silico hypothesis and assess compound selectivity. Four compounds were identified as selective TRPM8 antagonists, of which two were dual-acting TRPM8/TRPV1 modulators. The most potent TRPM8 antagonists ( BB 0322703 and BB 0322720 ) underwent molecular modelling studies to highlight key structural features responsible for drug-protein interaction. The two compounds were also investigated by patch-clamp assays, confirming low micromolar potencies. The most potent compound ( BB 0322703 , IC 50 1.25 ± 0.26 μM) was then profiled in vivo in a cold allodinya model, showing pharmacological efficacy at 30 μM dose. The new chemotypes identified showed remarkable pharmacological properties paving the way to further investigations for drug discovery and pharmacological purposes. |
