Mechanism of action: N-methyl-D-aspartate (NMDA) receptor, low-trapping, open-channel blocker
AZD6765 binds within the NMDA channel pore (Ki 0.5-3μM) and functionally blocks the flow of charged ions through recombinant human NR2A and NR2B receptor complexes (IC50 4 to 40μM), as reported throughout various literature references. Different from classic NMDA channel blockers (ketamine and MK801), AZD6765 is rapidly reversible (fast off-rate, 2.8 seconds, and low-trapping, 52-59%) which is believed to underlie an improved safety/efficacy profile. Elevations in cortical gamma wave EEG across multiple species (mouse, rat, and non-human primates), characteristic of non-selective NMDA channel blockage, occurs at plasma exposures that overlap with efficacy (1 to 5μM) and represent a useful biomarker for demonstrating central target engagement in the clinical setting.
Relative to projected therapeutic concentrations, AZD6765 has >10-fold margins to elevations in locomotor activity and other behavioral abnormalities (head weaving, retropulsion, and ataxia) typically associated with the psychotomimetic liabilities of the NMDA class. At targeted plasma concentrations (1 to 5μM), AZD6765 produces changes in behavioral performance consistent with mild and transient reductions in attention/vigilance. However, at targeted concentrations, there is no evidence for learning and/or memory deficits following either acute or sub-chronic dosing.
Safety and tolerability
Overall in 15+ clinical studies comprising >700 subjects, AZD6765 has been given to healthy volunteers, subjects with renal impairment, or patients with stroke, sleep apnoea, or major depressive disorder in single i.v. infusions (1 to 350mg) or multiple iv infusions (loading doses between 120 and approximately 460mg plus maintenance doses of up to 120mg every 8 hours for 3 days; 100 or 150mg, 3 times weekly for 3 weeks). The most common adverse effects observed have been CNS-type, including dizziness, orthostatic hypotension, and transient increases in blood pressure.
Preclinical 3, 6 and 9 month intermittent i.v. infusion studies have been performed to support >45 infusions in humans. NMDA-class associated neurotoxicity findings have been observed in rats at supra-therapeutic doses.
Following i.v. infusion administration (up to 1 hour), AZD6765 reaches maximum plasma concentration (Cmax) at the end of the infusion and clears slowly from the body with a total clearance (CL) of approximately 0.13 L/h/kg and a half-life of about 13 hours. Since renal CL is one of the major routes of elimination (accounting for approximately ¼ of total CL), mild to moderate renal impairment had some effects on the PK of AZD6765.
Quantitative EEG and functional MRI (fMRI) have been used to guide dose for subsequent efficacy studies.
Suitable for and exclusions
The reproductive toxicology package indicates a risk of foetal toxicity. The inclusion of women of child-bearing potential would need to be assessed for any proposal based on the risk benefit and the use of appropriate highly effective contraception.
AZD6765 is CNS penetrant (see above) and, thus, suitable for appropriate CNS indications.
Pediatric disease projects will be considered assuming a favorable risk benefit setting. To date no juvenile nonclinical toxicology studies have been conducted with AZD6765.
Clinical trials for this compound
See all of the clinical trials currently associated with this compound:
Publications for this compound
Find out more about this compound by reading related publications:
Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects
A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression
Gene information from the NCBi
This compound works on the following genes: