2. Academic Validation
  3. Heteroaromatic salvinorin A analogue (P-3 l) elicits antinociceptive and anxiolytic-like effects

Heteroaromatic salvinorin A analogue (P-3 l) elicits antinociceptive and anxiolytic-like effects

  • Fitoterapia. 2023 Jun:167:105488. doi: 10.1016/j.fitote.2023.105488.
Caroline V L Moreira 1,  Ana Luiza G Faria 1,  Daiany P B Silva 1,  Paulo César Ghedini 1,  José Luis Rodrigues Martins 2,  Adam W Keasling 3,  Jordan K Zjawiony 4,  Pankaj Pandey 5,  Robert J Doerksen 4,  Hamilton B Napolitano 6,  Fábio F da Rocha 7,  Elson A Costa 1,  James O Fajemiroye 8
Affiliations

Affiliations

  • 1 Instituto de Ciências Biológicas, Universidade Federal de Goiás, 74001-970 Goiânia, GO, Brazil.
  • 2 Instituto de Ciências Biológicas, Universidade Federal de Goiás, 74001-970 Goiânia, GO, Brazil; Graduate Program in Pharmaceutical Sciences, Campus Arthur Wesley Archibald, Evangelical University of Goiás, Anápolis 75083-515, Brazil.
  • 3 Department of Chemistry, Andrew College, Cuthbert, GA 39840, USA.
  • 4 Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
  • 5 Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA; National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
  • 6 Grupo de Química Teórica e Estrutural de Anápolis, Universidade Estadual de Goiás, 75001-970 Anápolis, GO, Brazil; Graduate Program in Pharmaceutical Sciences, Campus Arthur Wesley Archibald, Evangelical University of Goiás, Anápolis 75083-515, Brazil.
  • 7 Department of Physiological Sciences, Institute of Biology, Federal Rural University of Rio de Janeiro, Seropédica, RJ, Brazil.
  • 8 Instituto de Ciências Biológicas, Universidade Federal de Goiás, 74001-970 Goiânia, GO, Brazil; Graduate Program in Pharmaceutical Sciences, Campus Arthur Wesley Archibald, Evangelical University of Goiás, Anápolis 75083-515, Brazil. Electronic address: jamesfajemiroye@ufg.br.
PMID: 36990290 DOI: 10.1016/j.fitote.2023.105488
Abstract

Previous studies have attributed the prominent analgesic, hallucinogenic, sedative, and anxiolytic properties of Salvia divinorum to Salvinorin A. However, the overall pharmacological profile of this isolate limits its clinical applications. To address these limitations, our study evaluates the C(22)-fused-heteroaromatic analogue of salvinorin A [2-O-salvinorin B benzofuran-2-carboxylate] (P-3l) in mice nociception and anxiety models while assessing possible mechanism of action. In comparison with the control group, orally administered P-3l (1, 3, 10, and 30 mg/kg) attenuates acetic acid-induced abdominal writhing, formalin-induced hind paw licking, the thermal reaction to the hotplate, and/or aversive response in the elevated plus-maze, open field, and light-dark box; and potentiates the effect of morphine and diazepam at sub-effective doses (1.25 and 0.25 mg/kg, respectively) without eliciting significant alterations in relative organ weight, or haematological or biochemical parameters. The in vivo blockade of P-3 l effects by naloxone (non-selective Opioid Receptor Antagonist), naloxonazine (antagonist of specific subtypes mu1 of μ-OR), and nor-binaltorphimine (selective ĸ-OR antagonist) supports initial results from binding assays and the interpretations made possible from computational modeling of the interactions of P-3 l with the Opioid Receptor subtypes. In addition to the opioidergic mechanism, the blockade of the P-3 l effect by flumazenil suggests benzodiazepine binding site involvement in its biological activities. These results support P-3 l potentially possessing clinical utility and substantiate the need for additional pharmacological characterization.

Keywords

Antinociceptive; Anxiolytic; Benzodiazepine site; Docking; Opioid receptors; P-3 l; Salvinorin.

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