Flunitrazepam–Membrane Binding: A Sensor for Drug-Induced GABAA-R and Membrane Structure Changes

Abstract

Flunitrazepam (FNZ) is a sedative–hypnotic benzodiazepine with important therapeutic usefulness and significant abuse liability. Its capability to induce anterograde amnesia favors FNZ use as a “date-rape drug” administered often at a bar or party (“club drug”) by adding it unknowingly to the drinks of victims who will have limited memory of the assault. On the contrary, on the illicit market, “FNZ preparations” may be fake products that do not contain that substance. FNZ combined with anesthetics, opioids, ethanol, cocaine, and methamphetamine can occur in therapeutic use and in polydrug abuse. The FNZ action mechanism involves its binding to the γ-aminobutyric acid receptor (GABAA-R), an intrinsic membrane protein. Changes in the binding site structure by allosteric binding of another drug or by affecting lipid phase dynamics in a receptor's surroundings can modulate this binding activity. Thus, FNZ–GABAA-R binding may serve to sense FNZ concentration, GABAA-R environment organization, and FNZ interaction with other drugs, including polydrug use or abuse conditions.