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 (σR) antagonism, could be an opioid adjuvant strategy. The in vitro σR and σR profiles of previous synthesized MOR/DOR agonists (-)-2/-LP2 (), (-)-2-LP2 (), and (-)-2-LP2 () were assayed. To investigate the pivotal role of -normetazocine stereochemistry, we also synthesized the (+)-2/-LP2 (), (+)-2-LP2 (), and (+)-2-LP2 () compounds. (-)-2/-LP2 (), (-)-2-LP2 (), and (-)-2-LP2 () compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2/-LP2 (), (+)-2-LP2 (), and (+)-2-LP2 () 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-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2/-LP2 (), 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 -normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413390PMC
http://dx.doi.org/10.3390/molecules27165135DOI Listing

Publication Analysis

Top Keywords

-normetazocine derivatives
8
--2/-lp2 --2-lp2
8
--2-lp2 --2-lp2
8
+-2/-lp2 +-2-lp2
8
+-2-lp2 +-2-lp2
8
formalin test
8
opioid
6
--2-lp2
5
novel -normetazocine
4
derivatives opioid
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!