Azd-3043

Abstract

Background Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acidA (GABAA) receptor containing a metabolically-labile ester moiety. We postulated that its metabolic pathway would result in a short acting clinical profile. Methods The effects of AZD-3043, propofol and propanidid were studied on GABAA receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous (IV) administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. Results AZD-3043 potentiated GABAA receptor-mediated chloride currents and inhibited [35S]tert-butylbicyclophosphorothionate binding to GABAA receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared to propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. Conclusions AZD-3043 is a positive allosteric modulator of the GABAA receptor in vitro and a sedative/hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative/hypnotic agent with rapid and predictable recovery.

Propofol and AZD3043 Inhibit Adult Muscle and Neuronal Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes

“…The effect of AZD3043 on nAChR has not been investigated before [ 14 ], but is more potent in inhibition of the adult muscle nAChR compared to propofol. AZD3043 shares the same properties as propofol in terms of inhibition of the α3β2 nAChR subtype, but lacks the positive modulation of the α7 subtype seen with propofol although the IC 50 values were similar.…”

“…Flood and co-workers have previously demonstrated that propofol has a low sensitivity for the α7 nAChR subtype but it has not been investigated whether propofol interacts with the adult α1β1δε subtype or the presynaptic α3β2 nAChR subtype. AZD3043 is a new rapid acting intravenous anesthetic agent currently in clinical trials and with similar effects as propofol on the GABA A receptor, but the affinity for other receptor types has not been investigated in detail [ 13 , 14 ]. Thus, it has not been investigated whether AZD3043 inhibits nAChRs in the NMJ or how much muscle relaxation ADZ3043-based anesthesia provides.…”

Synthesis and Evaluation of Fluorine-Substituted Phenyl Acetate Derivatives as Ultra-Short Recovery Sedative/Hypnotic Agents

“…The maximum potentiation achieved by compound 5j (EC 50  = 12.0 µM) was approximately 50% of that produced by propofol (EC 50  = 2.4 µM) and 150% of that of propanidid (EC 50  = 25.2 µM) (Figure 7) (EC 50 value of AZD3043 was 36 µM [6]). …”

Phenyl acetate derivatives, fluorine-substituted on the phenyl group, as rapid recovery hypnotic agents with reflex depression

“…6.5.6. Hypnosis in response to intravenous (IV) infusion [19] Induction of hypnosis in rats were achieved using 2 Â HD 50 dose of test compound, and immediately after induction, infusion via the tail vein was commenced at HD 50 dosage per min. the infusion rate was maintained for 20 min or 1 h or 3 h later.…”