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Papers of the Week

Papers: 28 Nov 2020 - 4 Dec 2020

Animal Studies, Pharmacology/Drug Development

2020 Dec 02

ACS Chem Neurosci

Identification of a Potent and Selective 5-HT Receptor Agonist with and Antinociceptive Activity.


Linciano P, Sorbi C, Comitato A, Lesniak A, Bujalska-Zadrożny M, Pawłowska A, Bielenica A, Orzelska-Górka J, Kędzierska E, Biała G, Ronsisvalle S, Limoncella S, Casarini L, Cichero E, Fossa P, Satała G, Bojarski AJ, Brasili L, Bardoni R, Franchini S
ACS Chem Neurosci. 2020 Dec 02.
PMID: 33263393.


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-HTR 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-HTR agonists -[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate () and -((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate () and . The role of chirality in the interaction with 5-HTR was evaluated by molecular docking. The activity of the was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). 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-HTR antagonist, WAY-100635. The eutomer ()-, 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, ()- evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than -. The eutomer ()- showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, ()- 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.