Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT1AR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT1AR agonists N-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate (rac-1) and N-((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1H-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate (rac-2) in vitro and in vivo. The role of chirality in the interaction with 5-HT1AR was evaluated by molecular docking. The activity of the rac-1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac-1 was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT1AR antagonist, WAY-100635. The eutomer (S)-1, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, (S)-1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac-1. The eutomer (S)-1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, (S)-1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.

Identification of a Potent and Selective 5-HT1AReceptor Agonist with In Vitro and In Vivo Antinociceptive Activity / Linciano, P.; Sorbi, C.; Comitato, A.; Lesniak, A.; Bujalska-Zadrozny, M.; Pawlowska, A.; Bielenica, A.; Orzelska-Gorka, J.; Kedzierska, E.; Biala, G.; Ronsisvalle, S.; Limoncella, S.; Casarini, L.; Cichero, E.; Fossa, P.; Satala, G.; Bojarski, A. J.; Brasili, L.; Bardoni, R.; Franchini, S.. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - 11:24(2020), pp. 4111-4127. [10.1021/acschemneuro.0c00289]

Identification of a Potent and Selective 5-HT1AReceptor Agonist with In Vitro and In Vivo Antinociceptive Activity

Linciano P.;Sorbi C.;Comitato A.;Limoncella S.;Casarini L.;Brasili L.;Bardoni R.;Franchini S.
2020

Abstract

Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT1AR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT1AR agonists N-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate (rac-1) and N-((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1H-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate (rac-2) in vitro and in vivo. The role of chirality in the interaction with 5-HT1AR was evaluated by molecular docking. The activity of the rac-1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac-1 was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT1AR antagonist, WAY-100635. The eutomer (S)-1, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, (S)-1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac-1. The eutomer (S)-1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, (S)-1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.
11
24
4111
4127
Identification of a Potent and Selective 5-HT1AReceptor Agonist with In Vitro and In Vivo Antinociceptive Activity / Linciano, P.; Sorbi, C.; Comitato, A.; Lesniak, A.; Bujalska-Zadrozny, M.; Pawlowska, A.; Bielenica, A.; Orzelska-Gorka, J.; Kedzierska, E.; Biala, G.; Ronsisvalle, S.; Limoncella, S.; Casarini, L.; Cichero, E.; Fossa, P.; Satala, G.; Bojarski, A. J.; Brasili, L.; Bardoni, R.; Franchini, S.. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - 11:24(2020), pp. 4111-4127. [10.1021/acschemneuro.0c00289]
Linciano, P.; Sorbi, C.; Comitato, A.; Lesniak, A.; Bujalska-Zadrozny, M.; Pawlowska, A.; Bielenica, A.; Orzelska-Gorka, J.; Kedzierska, E.; Biala, G.; Ronsisvalle, S.; Limoncella, S.; Casarini, L.; Cichero, E.; Fossa, P.; Satala, G.; Bojarski, A. J.; Brasili, L.; Bardoni, R.; Franchini, S.
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