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

Abstract The pivotal role of the stereocenter at the N -substituent of the 6,7-benzomorphan scaffold was investigated combining synthetic and pharmacological approaches. 2 R - and 2 S -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, 2 S -LP2 ( 5 ) showed an improved pharmacological profile in comparison to LP2 ( 1 ) and 2 R -LP2 ( 4 ). 2 S -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 2 S -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. 2 S -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 2 S -LP2 ( 5 ) biased multitarget MOR/DOR agonist could provide a safer treatment opportunity.