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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Designer Benzodiazepines’ Activity on Opioid Receptors: A Docking Study

Author(s): Valeria Catalani*, Michelle Botha, John Martin Corkery, Amira Guirguis, Alessandro Vento and Fabrizio Schifano

Volume 28, Issue 32, 2022

Published on: 22 September, 2022

Page: [2639 - 2652] Pages: 14

DOI: 10.2174/1381612828666220510153319

Price: $65

Abstract

Background: Previous studies have reported that benzodiazepines (BZDs) seem to enhance euphoric and reinforcing properties of opioids in opioid users so that a direct effect on opioid receptors has been postulated, together with a possible synergistic induction of severe side effects due to co use of BDZs and opioids. This is particularly worrisome given the appearance on the market of designer benzodiazepines (DBZDs), whose activity/toxicity profiles are scarcely known.

Objectives: This study aimed to evaluate, through computational studies, the binding affinity (or lack thereof) of 101 DBZDs identified online on the kappa, mu, and delta opioid receptors (K, M, DOR); and to assess whether their mechanism of action could include activation of the latter.

Methods: MOE® was used for the computational studies. Pharmacophore mapping based on strong opioids agonist binders’ 3D chemical features was used to filter the DBZDs. Resultant DBZDs were docked into the crystallised 3D active conformation of KOR (PDB6B73), DOR (PDB6PT3) and MOR (PDB5C1M). Co-crystallised ligands and four strong agonists were used as reference compounds. A score (S, Kcal/mol) representative of the predicted binding affinity, and a description of ligand interactions were obtained from MOE®.

Results: The docking results, filtered for S < -8.0 and the interaction with the Asp residue, identified five DBZDs as putative binders of the three ORs : ciclotizolam, fluloprazolam, JQ1, Ro 48-6791, and Ro 48-8684.

Conclusion: It may be inferred that at least some DBZDs may have the potential to activate opioid receptors. This could mediate/increase their anxiolytic, analgesic, and addiction potentials, as well as worsen the side effects associated with opioid co-use.

Keywords: Designer benzodiazepines, docking, pharmacophore mapping, NPSfinder®, Kappa-delta-mu opioid receptors, MOE®.

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