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Papers of the Week

Papers: 27 Aug 2022 - 2 Sep 2022

Pharmacology/Drug Development

2022 Aug 12




Novel N-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain.


Turnaturi R, Chiechio S, Pasquinucci L, Spoto S, Costanzo G, Dichiara M, Piana S, Grasso M, Amata E, Marrazzo A, Parenti C
Molecules. 2022 Aug 12; 27(16).
PMID: 36014375.


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.