The channel protein Panx-1 is involved in some pathologies, such as epilepsy, ischemic stroke, cancer and Parkinson’s disease, as well as in neuropathic pain. These observations make Panx-1 an interesting biological target. We previously published some potent indole derivatives as Panx-1 blockers, and as continuation of the research in this field we report here the studies on additional chemical scaffolds, naphthalene and pyrazole, appropriately substituted with those functions that gave the best results as in our indole series (sulphonamide functions and one/two carboxylic groups) and in Panx-1 blockers reported in the literature (sulphonic acid). Compounds 4 and 13, the latter being an analogue of the drug Probenecid, are the most potent Panx-1 blockers obtained in this study, with I = 97% and I = 93.7% at 50 M, respectively. Both compounds, tested in a mouse model of oxaliplatin-induced neuropathic pain, showed a similar anti-hypersensitivity profile and are able to significantly increase the mouse pain threshold 45 min after the injection of the doses of 1 nmol and 3 nmol. Finally, the molecular dynamic studies and the PCA analysis have made it possible to identify a discriminating factor able to separate active compounds from inactive ones.

New Panx-1 Blockers: Synthesis, Biological Evaluation and Molecular Dynamic Studies / Crocetti, Letizia; Guerrini, Gabriella; Giovannoni, Maria Paola; Melani, Fabrizio; Lamanna, Silvia; Di Cesare Mannelli, Lorenzo; Lucarini, Elena; Ghelardini, Carla; Wang, Junjie; Dahl, Gerhard. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - ELETTRONICO. - 23:(2022), pp. 4827-4855. [10.3390/ijms23094827]

New Panx-1 Blockers: Synthesis, Biological Evaluation and Molecular Dynamic Studies

Crocetti, Letizia;Guerrini, Gabriella;Giovannoni, Maria Paola
;
Melani, Fabrizio;Lamanna, Silvia;Di Cesare Mannelli, Lorenzo;Lucarini, Elena;Ghelardini, Carla;
2022

Abstract

The channel protein Panx-1 is involved in some pathologies, such as epilepsy, ischemic stroke, cancer and Parkinson’s disease, as well as in neuropathic pain. These observations make Panx-1 an interesting biological target. We previously published some potent indole derivatives as Panx-1 blockers, and as continuation of the research in this field we report here the studies on additional chemical scaffolds, naphthalene and pyrazole, appropriately substituted with those functions that gave the best results as in our indole series (sulphonamide functions and one/two carboxylic groups) and in Panx-1 blockers reported in the literature (sulphonic acid). Compounds 4 and 13, the latter being an analogue of the drug Probenecid, are the most potent Panx-1 blockers obtained in this study, with I = 97% and I = 93.7% at 50 M, respectively. Both compounds, tested in a mouse model of oxaliplatin-induced neuropathic pain, showed a similar anti-hypersensitivity profile and are able to significantly increase the mouse pain threshold 45 min after the injection of the doses of 1 nmol and 3 nmol. Finally, the molecular dynamic studies and the PCA analysis have made it possible to identify a discriminating factor able to separate active compounds from inactive ones.
2022
23
4827
4855
Goal 3: Good health and well-being
Crocetti, Letizia; Guerrini, Gabriella; Giovannoni, Maria Paola; Melani, Fabrizio; Lamanna, Silvia; Di Cesare Mannelli, Lorenzo; Lucarini, Elena; Ghelardini, Carla; Wang, Junjie; Dahl, Gerhard
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1267468
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