Novel N-normetazocine derivatives with opioid Agonist/Sigma-1 receptor antagonist profile as potential analgesics in inflammatory pain

Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (sigma R-1) antagonism, could be an opioid adjuvant strategy. The in vitro sigma R-1 and sigma R-2 profiles of previous synthesized MOR/DOR agonists (-)-2R/S-LP2 (1), (-)-2R-LP2 (2), and (-)-2S-LP2 (3) were assayed. To investigate the pivotal role of N-normetazocine stereochemistry, we also synthesized the (+)-2R/S-LP2 (7), (+)-2R-LP2 (8), and (+)-2S-LP2 (9) compounds. (-)-2R/S-LP2 (1), (-)-2R-LP2 (2), and (-)-2S-LP2 (3) compounds have Ki values for sigma 1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/sigma 1R profile. Instead, (+)-2R/S-LP2 (7), (+)-2R-LP2 (8), and (+)-2S-LP2 (9) isomers displayed a nanomolar affinity for sigma 1R, with significative selectivity vs. sigma 2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (-)-2S-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The sigma 1R selective compound (+)-2R/S-LP2 (7), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist sigma 1R profile. The multitarget or single target profile of assayed N-normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.