Identification of a Potent and Selective 5-HT1A Receptor Agonist with In Vitro and In Vivo Antinociceptive Activity.

Anna Bielenica,Magdalena Bujalska‐Zadrożny ,Grzegorz Satała,Agata Pawłowska,Pasquale Linciano,Rita Bardoni,Grażyna Biała,Livio Brasili,Anna Leśniak ,Jolanta Orzelska‐Górka ,Claudia Sorbi,Elena Cichero,Livio Casarini,Andrzej J Bojarski,Ewa Kędzierska,Simone Ronsisvalle,Silvia Limoncella,Paola Fossa,Antonella Comitato,Silvia Franchini

doi:10.1021/acschemneuro.0c00289

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.

Highlights

Acute and chronic pain, both nociceptive and neuropathic, are involved in many illnesses and conditions, posing a great challenge to public health
All seven types of serotoninergic receptors (5-HTRs), including various isoforms, are present in the spinal cord, where they play complex roles in modulating pain.3 5-HT1ARs are highly expressed throughout the pain neuroaxis where they exert a clear antinociceptive action by inhibiting the transmission of nociceptive signals.[3]
The tested compounds were synthesized as previously reported with slight modifications.[28] (S)- and (R)-1 and 2 were prepared as oxalate salts by reaction of the corresponding enantiopure free amines (S)/(R)-3 and (S)/(R)

Summary

Introduction

Both nociceptive and neuropathic, are involved in many illnesses and conditions, posing a great challenge to public health. All seven types of serotoninergic receptors (5-HTRs), including various isoforms, are present in the spinal cord, where they play complex roles in modulating pain.3 5-HT1ARs are highly expressed throughout the pain neuroaxis where they exert a clear antinociceptive action by inhibiting the transmission of nociceptive signals.[3] full and partial 5-HT1AR agonists have shown to be effective in the treatment of pain.[4−7] In addition, the use of 5-HT1A agonists in combination with opioids could be advantageous, since they are able to reduce addiction, by decreasing the reward effects of opioids[8] and to revert opioid-induced respiratory depression.[9]

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Results

Conclusion