(+)-and (−)-Phenazocine enantiomers: evaluation of their dual opioid agonist/σ1 antagonist properties and antinociceptive effects

cis-N-Substituted N-normetazocine enantiomers possess peculiar pharmacological profiles. Indeed, dextro enantiomers bind with high affinity 1 receptor while opposite enantiomers bind opioid receptors. In spite of their stereochemistry, cis-N-2-phenylethyl N-normetazocine (phenazocine) enantiomers showed mixed opioid/1 receptor profiles and a significant in vivo analgesia. To the best of our knowledge, there is no information available regarding the evaluation of 1 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 1 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 1 receptor affinity of (+)-and (−)-phenazocine (Ki = 3.8 ± 0.4 nM, Ki = 85 ± 2.0 nM, respectively) suggesting a 1 antagonist profile of both enantiomers. This 1 antagonistic component of two phenazocine enantiomers was corroborated by in vivo studies in which the selective 1 receptor agonist PRE-084, was able to unmask their 1 antagonistic component associated with the opioid activity.The 1 antagonistic component of (+)- and (−)-phenazocine may justify their analgesic activity and it suggests that they may constitute a useful scaffold to develop new ligands with this dual activity.