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

• Published in: European journal of medicinal chemistry Vol. 125; pp. 603 - 610
• Main Authors: Prezzavento, O., Arena, E., Sánchez-Fernández, C., Turnaturi, R., Parenti, C., Marrazzo, A., Catalano, R., Amata, E., Pasquinucci, L., Cobos, E.J.
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 05.01.2017
• Subjects: (+)-Phenazocine; (−)-Phenazocine; Bifunctional ligand; Mechanical antinociception; Opioid; Sigma-1 receptor; Mechanical antinociception; Opioid; Sigma-1 receptor; (−)-Phenazocine; Bifunctional ligand; (+)-Phenazocine
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.09.077

cis-N-Substituted N-normetazocine enantiomers possess peculiar pharmacological profiles. Indeed, dextro enantiomers bind with high affinity σ1 receptor while opposite enantiomers bind opioid receptors. In spite of their stereochemistry, cis-N-2-phenylethyl N-normetazocine (phenazocine) enantiomers showed mixed opioid/σ1 receptor profiles and a significant in vivo analgesia. To the best of our knowledge, there is no information available regarding the evaluation of σ1 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 σ1 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 σ1 receptor affinity of (+)-and (−)-phenazocine (Ki = 3.8 ± 0.4 nM, Ki = 85 ± 2.0 nM, respectively) suggesting a σ1 antagonist profile of both enantiomers. This σ1 antagonistic component of two phenazocine enantiomers was corroborated by in vivo studies in which the selective σ1 receptor agonist PRE-084, was able to unmask their σ1 antagonistic component associated with the opioid activity. The σ1 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. [Display omitted] •We investigated the σ1 pharmacological profile of Phenazocine enantiomers.•We improved the plethora of information about the analgesic activity of Phenazocine.•We employed phenytoin as σ1 receptor positive allosteric modulator.•PRE-084 unmasked σ1 antagonistic component of (+)- and (−)- phenazocine.•(+) and (−)-Phenazocine display σ1 antagonist activity and opioid analgesia.