Designer Benzodiazepines' Activity on Opioid Receptors: A Docking Study

Area of Science:

• Pharmacology
• Computational Chemistry
• Medicinal Chemistry

Background:

• Benzodiazepines (BZDs) may enhance opioid effects, raising concerns about co-use.
• Designer benzodiazepines (DBZDs) have unknown activity and toxicity profiles.
• Co-use of BZDs and opioids can lead to severe side effects.

Purpose of the Study:

• To computationally evaluate the binding affinity of 101 online-identified DBZDs to kappa, mu, and delta opioid receptors (KOR, MOR, DOR).
• To assess if DBZDs' mechanism of action involves activating opioid receptors.
• To identify specific DBZDs that may interact with opioid receptors.

Main Methods:

• Utilized Molecular Operating Environment (MOE®) for computational studies.
• Applied pharmacophore mapping to filter DBZDs based on opioid agonist features.
• Performed molecular docking of filtered DBZDs into KOR, MOR, and DOR crystal structures.

Main Results:

• Identified five DBZDs (ciclotizolam, fluloprazolam, JQ1, Ro 48-6791, Ro 48-8684) as potential binders to all three opioid receptors.
• Docking results showed binding affinity scores (S) below -8.0 Kcal/mol for these compounds.
• Key interactions with the Asp residue were observed for the identified DBZDs.

Conclusions:

• At least some DBZDs show potential for activating opioid receptors.
• This activation could enhance anxiolytic, analgesic, and addiction potentials of DBZDs.
• DBZD interaction with opioid receptors may exacerbate side effects in co-users.