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

Prezzavento, Orazio; Arena, Elena; Sánchez-Fernández, Cristina; Turnaturi, Rita; Parenti, Carmela; Marrazzo, Agostino; Catalano, Roberto; Amata, Emanuele; Pasquinucci, Lorella; Cobos, Enrique J.

doi:10.1016/j.ejmech.2016.09.077

Cited by 42 publications

(34 citation statements)

References 42 publications

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“…This is consistent with both frequency of contacts and the most important terms of the interaction energy ( Figure 5 b). Also, S -PHZ, which exhibits one of the highest K i in the studied series, 61.7 nM [ 23 ], is characterized by almost the smallest number of contacts and the smallest interaction energy terms in the presented calculations ( Figure 5 b). On the other hand, the HALO ligand, which is the strongest σ 1 receptor antagonist considered here (K i = 0.65 nM [ 13 ]) exhibits the second highest number of contacts and the attractive energy term.…”

Section: Resultsmentioning

confidence: 99%

“…The experimental studies indicate that ligands have been classified as agonists or antagonists on the basis of their effects in animals. Whereas the benzomorphans are classified as agonists, ligands such as haloperidol are marked as antagonists [ 2 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…These compounds are alkyl and arylcarboxamide derivatives [ 32 ], arylalkylamines [ 30 ], benzoxazolones, and dioxolane-based compounds [ 33 ]. The enantiopreference toward compounds was also studied [ 23 , 29 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

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Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations

et al. 2018

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Despite considerable advances over the past years in understanding the mechanisms of action and the role of the σ1 receptor, several questions regarding this receptor remain unanswered. This receptor has been identified as a useful target for the treatment of a diverse range of diseases, from various central nervous system disorders to cancer. The recently solved issue of the crystal structure of the σ1 receptor has made elucidating the structure–activity relationship feasible. The interaction of seven representative opioid ligands with the crystal structure of the σ1 receptor (PDB ID: 5HK1) was simulated for the first time using molecular dynamics (MD). Analysis of the MD trajectories has provided the receptor–ligand interaction fingerprints, combining information on the crucial receptor residues and frequency of the residue–ligand contacts. The contact frequencies and the contact maps suggest that for all studied ligands, the hydrophilic (hydrogen bonding) interactions with Glu172 are an important factor for the ligands’ affinities toward the σ1 receptor. However, the hydrophobic interactions with Tyr120, Val162, Leu105, and Ile124 also significantly contribute to the ligand–receptor interplay and, in particular, differentiate the action of the agonistic morphine from the antagonistic haloperidol.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations

et al. 2018

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“…Several synthetic small molecules with different structures bind with high affinity and selectivity to the σ 1 receptor. The σ 1 receptor agonists have shown neuroprotective, antiamnestic, and antidepressant effects; in contrast, the σ 1 receptor antagonists possess modulatory effects on opioid analgesia, as well as antiproliferative and antiangiogenic activities [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

A Structure- and Ligand-Based Virtual Screening of a Database of “Small” Marine Natural Products for the Identification of “Blue” Sigma-2 Receptor Ligands

et al. 2018

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Sigma receptors are a fascinating receptor protein class whose ligands are actually under clinical evaluation for the modulation of opioid analgesia and their use as positron emission tomography radiotracers. In particular, peculiar biological and therapeutic functions are associated with the sigma-2 (σ2) receptor. The σ2 receptor ligands determine tumor cell death through apoptotic and non-apoptotic pathways, and the overexpression of σ2 receptors in several tumor cell lines has been well documented, with significantly higher levels in proliferating tumor cells compared to quiescent ones. This acknowledged feature has found practical application in the development of cancer cell tracers and for ligand-targeting therapy. In this context, the development of new ligands that target the σ2 receptors is beneficial for those diseases in which this protein is involved. In this paper, we conducted a search of new potential σ2 receptor ligands among a database of 1517 “small” marine natural products constructed by the union of the Seaweed Metabolite and the Chemical Entities of Biological Interest (ChEBI) Databases. The structures were passed through two filters that were constituted by our developed two-dimensional (2D) and three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) statistical models, and successively docked upon a σ2 receptor homology model that we built according to the FASTA sequence of the σ2/TMEM97 (SGMR2_HUMAN) receptor.

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“…The σ 1 receptor agonists have showed neuroprotective, anti-amnestic and antidepressant effects [12–14]. Conversely, σ 1 receptor antagonists are considered antiproliferative, antiangiogenic and to have modulatory effects on opioid analgesia [15–17]. Some studies suggested that σ 1 receptor is involved in modulating the synthesis and release of dopamine and also to act as a molecular chaperone at the mitochondrion-associated endoplasmic reticulum membrane (MAM) where it regulates calcium signaling between the two organelles [4, 18–20].…”

Section: Introductionmentioning

confidence: 99%

S2RSLDB: a comprehensive manually curated, internet-accessible database of the sigma-2 receptor selective ligands

et al. 2017

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Background Sigma (σ) receptors are accepted as a particular receptor class consisting of two subtypes: sigma-1 (σ1) and sigma-2 (σ2). The two receptor subtypes have specific drug actions, pharmacological profiles and molecular characteristics. The σ2 receptor is overexpressed in several tumor cell lines, and its ligands are currently under investigation for their role in tumor diagnosis and treatment. The σ2 receptor structure has not been disclosed, and researchers rely on σ2 receptor radioligand binding assay to understand the receptor’s pharmacological behavior and design new lead compounds.Description Here we present the sigma-2 Receptor Selective Ligands Database (S2RSLDB) a manually curated database of the σ2 receptor selective ligands containing more than 650 compounds. The database is built with chemical structure information, radioligand binding affinity data, computed physicochemical properties, and experimental radioligand binding procedures. The S2RSLDB is freely available online without account login and having a powerful search engine the user may build complex queries, sort tabulated results, generate color coded 2D and 3D graphs and download the data for additional screening.ConclusionThe collection here reported is extremely useful for the development of new ligands endowed of σ2 receptor affinity, selectivity, and appropriate physicochemical properties. The database will be updated yearly and in the near future, an online submission form will be available to help with keeping the database widely spread in the research community and continually updated. The database is available at http://www.researchdsf.unict.it/S2RSLDB.Graphical abstract

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

Cited by 42 publications

References 42 publications

Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations

Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations

A Structure- and Ligand-Based Virtual Screening of a Database of “Small” Marine Natural Products for the Identification of “Blue” Sigma-2 Receptor Ligands

S2RSLDB: a comprehensive manually curated, internet-accessible database of the sigma-2 receptor selective ligands

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