(+)-and (-)-Phenazocine enantiomers: Evaluation of their dual opioid agonist/σ 1 antagonist properties and antinociceptive effects

cis-N-Substituted N-normetazocine enantiomers possess peculiar pharmacological profiles. Indeed, dextro enantiomers bind with high affinity σ receptor while opposite enantiomers bind opioid receptors. In spite of their stereochemistry, cis-N-2-phenylethyl N-normetazocine (phenazocine) enantiomers showed mixed opioid/σ receptor profiles and a significant in vivo analgesia. To the best of our knowledge, there is no information available regarding the evaluation of σ pharmacological profile in the antinociceptive effects of (+)- and (-)-phenazocine. Therefore, the present study was designed to ascertain this component by in vitro and in vivo studies. In particular, we tested the σ affinity of both enantiomers by a predictive binding assay in absence or presence of phenytoin (DPH). Our results showed that DPH (1 mM) did not increase the σ receptor affinity of (+)-and (-)-phenazocine (K = 3.8 ± 0.4 nM, K = 85 ± 2.0 nM, respectively) suggesting a σ antagonist profile of both enantiomers. This σ antagonistic component of two phenazocine enantiomers was corroborated by in vivo studies in which the selective σ receptor agonist PRE-084, was able to unmask their σ antagonistic component associated with the opioid activity. The σ antagonistic component of (+)- and (-)-phenazocine may justify their analgesic activity and it suggests that they may constitute useful lead compounds to develop new ligands with this dual activity.