| Summary: | 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 (σ<sub>1</sub>R) antagonism, could be an opioid adjuvant strategy. The in vitro σ<sub>1</sub>R and σ<sub>2</sub>R profiles of previous synthesized MOR/DOR agonists (−)-2<i>R</i>/<i>S</i>-LP2 (<b>1</b>), (−)-2<i>R</i>-LP2 (<b>2</b>), and (−)-2<i>S</i>-LP2 (<b>3</b>) were assayed. To investigate the pivotal role of <i>N</i>-normetazocine stereochemistry, we also synthesized the (+)-2<i>R</i>/<i>S</i>-LP2 (<b>7</b>), (+)-2<i>R</i>-LP2 (<b>8</b>), and (+)-2<i>S</i>-LP2 (<b>9</b>) compounds. (−)-2<i>R</i>/<i>S</i>-LP2 (<b>1</b>), (−)-2<i>R</i>-LP2 (<b>2</b>), and (−)-2<i>S</i>-LP2 (<b>3</b>) compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2<i>R</i>/<i>S</i>-LP2 (<b>7</b>), (+)-2<i>R</i>-LP2 (<b>8</b>), and (+)-2<i>S</i>-LP2 (<b>9</b>) isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (−)-2<i>S</i>-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2<i>R</i>/<i>S</i>-LP2 (<b>7</b>), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed <i>N</i>-normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.
|
|---|