Synthesis and Structure-Activity Relationships of LP1 Derivatives: N-Methyl-N-phenylethylamino Analogues as Novel MOR Agonists.

The opioid pharmacological profile of -(-)--normetazocine derivatives is deeply affected by the nature of their -substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an -phenylpropanamido substituent. LP1 derivatives - and - were characterized by flexible groups at the -substituent that allow them to reposition themselves relative to -(-)--normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays. Among the series, compound , with the best in vitro and in vivo profile, resulted a MOR agonist which displays a K of 6.1 nM in a competitive binding assay, and an IC value of 11.5 nM and an I of 72% in measurement of cAMP accumulation in HEK293 cells stably expressing MOR, with a slight lower efficacy than LP1. Moreover, in a mouse model of acute thermal nociception, compound intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED of 4.33 mg/kg. These results expand our understanding of the importance of -substituent structural variations in the opioid receptor profile of -(-)--normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment.