Exploiting the power of stereochemistry in drug action: 3-[(2S,6S,11S)-8-Hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide as potent sigma-1 receptor antagonist

Rita Turnaturi, Lorella Pasquinucci, Santina Chiechio, Margherita Grasso, Agostino Marrazzo, Emanuele Amata, Maria Dichiara, Orazio Prezzavento, Carmela Parenti

Research output: Contribution to journalArticlepeer-review

Abstract

(+)-(2S,6S,11S)- and (-)-(2R,6R,11R)-Benzomorphan derivatives have a different binding affinity for sigma-1 (σ1R) and opioid receptors, respectively. In this study, we describe the synthesis of the (+)-enantiomer [(+)-LP1] of the benzomorphan MOR agonist/DOR antagonist LP1 [(-)-LP1]. The binding affinity of both (+)-LP1 and (-)-LP1 for σ1R and sigma-2 receptor (σ2R) was tested. Moreover, (+)-LP1 opioid receptor binding affinity was also investigated. Finally, (+)-LP1 was tested in a mouse model of inflammatory pain. Our results showed a nanomolar σ1R and binding affinity for (+)-LP1. Both (+)-LP1 and (-)-LP1 elicited a significant analgesic effect in a formalin test. Differently from (-)-LP1, the analgesic effect of (+)-LP1 was not reversed by naloxone, suggesting a σ1R antagonist profile. Furthermore, σ1R agonist PRE-084 was able to unmask the σ1R antagonistic component of the benzomorphan compound. (+)-LP1 could constitute an useful lead compound to develop new analgesics based on mechanisms of action alternative to opioid receptor activation.

Original languageEnglish
Pages (from-to)999-1005
Number of pages7
JournalACS Chemical Neuroscience
Volume11
Issue number7
DOIs
Publication statusPublished - 2020

Keywords

  • Benzomorphan
  • Configuration
  • Formalin
  • Opioid
  • Pain
  • Sigma-2 receptor

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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