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

The opioid pharmacological profile ofcis-(-)-N-normetazocine derivatives is deeply affected by the nature of theirN-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 anN-phenylpropanamido substituent. LP1 derivatives5a-dand6a-dwere characterized by flexible groups at theN-substituent that allow them to reposition themselves relative tocis-(-)-N-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, compound5c, with the best in vitro and in vivo profile, resulted a MOR agonist which displays a KiMORof 6.1 nM in a competitive binding assay, and an IC50value of 11.5 nM and an Imaxof 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, compound5c,intraperitoneally administered, exhibits naloxone-reversed antinociceptive properties with an ED50of 4.33 mg/kg. These results expand our understanding of the importance ofN-substituent structural variations in the opioid receptor profile ofcis-(-)-N-normetazocine derivatives and identify a new MOR agonist useful for the development of novel opioid analgesics for pain treatment.