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

• Published in: European journal of medicinal chemistry Vol. 168; pp. 189 - 198
• Main Authors: Pasquinucci, Lorella, Turnaturi, Rita, Calò, Girolamo, Pappalardo, Francesco, Ferrari, Federica, Russo, Giulia, Arena, Emanuela, Montenegro, Lucia, Chiechio, Santina, Prezzavento, Orazio, Parenti, Carmela
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15.04.2019
• Subjects: Asymmetric synthesis; BRET; G-protein; Multitarget; Pain; Radioligand competition binding; Tail flick test; β-arrestin; BRET; GPI; Multitarget; SAR; DOR; Radioligand competition binding; i.p; KOR; MOR; Pain; Tail flick test; Asymmetric synthesis; β-arrestin; G-protein; MVD; TFL
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.02.043

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. [Display omitted] •The stereocenter role at the N-substituent of the 6,7-benzomorphan scaffold was investigated.•2R- and 2S-diastereoisomers of the multitarget opioid ligand LP2 were synthesized.•2S-LP2 showed a better pharmacological profile than 2R-LP2 in in vitro and in vivo assays.•2S-LP2 resulted a biased multitarget MOR/DOR agonist.•2S-LP2 elicited an antinociceptive potency 1.5- and 3-times higher than LP2 and R-antipode.