(2S)-N-2-methoxy-2-phenylethyl-6,7-benzomorphan compound (2S-LP2): Discovery of a biased mu/delta opioid receptor agonist

Lorella Pasquinucci, Rita Turnaturi, Girolamo Calò, Francesco Pappalardo, Federica Ferrari, Giulia Russo, Emanuela Arena, Lucia Montenegro, Santina Chiechio, Orazio Prezzavento, Carmela Parenti

Research output: Contribution to journalArticlepeer-review

Abstract

The pivotal role of the stereocenter at the N-substituent of the 6,7-benzomorphan scaffold was investigated combining synthetic and pharmacological approaches. 2R- and 2S-diastereoisomers of the multitarget MOR/DOR antinociceptive ligand LP2 (1) were synthesized and their pharmacological profile was evaluated in in vitro and vivo assays. From our results, 2S-LP2 (5) showed an improved pharmacological profile in comparison to LP2 (1) and 2R-LP2 (4). 2S-LP2 (5) elicited an antinociceptive effect with a 1.5- and 3-times higher potency than LP2 (1) and R-antipode (4), respectively. In vivo effect of 2S-LP2 (5) was consistent with the improved MOR/DOR efficacy profile assessed by radioligand binding assay, to evaluate the opioid receptor affinity, and BRET assay, to evaluate the capability to promote receptor/G-protein and receptor/β-arrestin 2 interaction. 2S-LP2 (5) was able to activate, with different efficacy, G-protein pathway over β-arrestin 2, behaving as biased agonist at MOR and mainly at DOR. Considering the therapeutic potential of both multitarget MOR/DOR agonism and functional selectivity over G-protein, the 2S-LP2 (5) biased multitarget MOR/DOR agonist could provide a safer treatment opportunity.

Original languageEnglish
Pages (from-to)189-198
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume168
DOIs
Publication statusPublished - Apr 15 2019

Keywords

  • Asymmetric synthesis
  • BRET
  • G-protein
  • Multitarget
  • Pain
  • Radioligand competition binding
  • Tail flick test
  • β-arrestin

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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