title: (+)-and (-)-Phenazocine enantiomers: Evaluation of their dual opioid agonist/σ1antagonist properties and antinociceptive effects.
abstract: cis-N-Substituted N-normetazocine enantiomers possess peculiar pharmacological profiles. Indeed, dextro enantiomers bind with high affinity σ1receptor while opposite enantiomers bind opioid receptors. In spite of their stereochemistry, cis-N-2-phenylethyl N-normetazocine (phenazocine) enantiomers showed mixed opioid/σ1receptor profiles and a significant in vivo analgesia. To the best of our knowledge, there is no information available regarding the evaluation of σ1pharmacological 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 σ1affinity 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 σ1receptor affinity of (+)-and (-)-phenazocine (Ki= 3.8 ± 0.4 nM, Ki= 85 ± 2.0 nM, respectively) suggesting a σ1antagonist profile of both enantiomers. This σ1antagonistic component of two phenazocine enantiomers was corroborated by in vivo studies in which the selective σ1receptor agonist PRE-084, was able to unmask their σ1antagonistic component associated with the opioid activity. The σ1antagonistic 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.
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. Electronic address: prezzave@unict.it.
authors.forename: O
authors.initials: O
authors.lastname: Prezzavento
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Arena
authors.affiliation: Department of Pharmacology, School of Medicine and Institute of Neuroscience, Biomedical Research Center, University of Granada, Parque Tecnológico de Ciencias de la Salud, 18100 Armilla, Granada, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Sánchez-Fernández
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Turnaturi
authors.affiliation: Department of Drug Sciences, Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Parenti
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Marrazzo
authors.affiliation: Department of Physics and Astronomy, University of Catania, Via S. Sofia 64, 95123 Catania, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Catalano
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Amata
authors.affiliation: Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Pasquinucci
authors.affiliation: Department of Pharmacology, School of Medicine and Institute of Neuroscience, Biomedical Research Center, University of Granada, Parque Tecnológico de Ciencias de la Salud, 18100 Armilla, Granada, Spain; Teófilo Hernando Institute for Drug Discovery, 28029, Madrid, Spain.
authors.forename: E J
authors.initials: EJ
authors.lastname: Cobos
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D051379:Mice; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D010620:Phenazocine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011957:Receptors, Opioid / Q000819:agonists*; D013237:Stereoisomerism
chemical_list: D000700:Analgesics; D009025:Morpholines; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; D010620:Phenazocine
keywords: (+)-Phenazocine; (−)-Phenazocine; Bifunctional ligand; Mechanical antinociception; Opioid; Sigma-1 receptor