Lanicemine

Lanicemine (AZD6765, formerly AR-R 15896AR) is a low-trapping, non-competitive N-methyl-D-aspartate (NMDA) receptor channel blocker that binds within the ion channel pore of NR2A- and NR2B-containing NMDA receptor complexes with micromolar affinity (Ki 0.5 to 2.1 micromolar; IC50 approximately 10 micromolar at resting membrane potential in rat cortical neurons). The compound is distinguished from the prototypical NMDA channel blocker ketamine by substantially lower channel trapping (54% versus 86%), a property that confers use-dependent, voltage-dependent blockade with preferential activity on tonically active neurons and minimal psychotomimetic liability. Originally synthesized by Astra (later AstraZeneca) as a neuroprotectant designated AR-R 15896AR, the compound advanced through Phase II trials for acute ischaemic stroke in 175 and 103 patients respectively before the stroke program was terminated owing to tolerability limitations at the high doses required for neuroprotective plasma concentrations. Following the demonstration of rapid antidepressant properties of ketamine in treatment-resistant major depressive disorder by Zarate and colleagues, AstraZeneca repositioned the compound for depression under the designation AZD6765 and the International Nonproprietary Name lanicemine.

The depression clinical program comprised four principal studies. A single-infusion crossover trial at the National Institute of Mental Health (n=22, 150 mg intravenous) demonstrated rapid but transient antidepressant effects (d=0.40 on the Montgomery-Asberg Depression Rating Scale) with no psychotomimetic effects compared to placebo. A Phase IIB repeated-dosing trial (n=152, three infusions in the published literature for three weeks) demonstrated sustained antidepressant efficacy at 100 mg (MADRS change minus 5.5 versus placebo, p=0.006) with minimal dissociative adverse events. However, a larger Phase IIb trial (n=302, 49 centers, four countries, 15 infusions over 12 weeks) at 50 mg and 100 mg doses adjunctive to ongoing antidepressant treatment failed to separate from placebo on the primary endpoint (MADRS change at week 6) or any secondary measure, resulting in program termination by AstraZeneca in 2013.

Pharmacokinetics following intravenous administration are described by a two-compartment model with low systemic clearance (8.1 to 9.4 L/h), a terminal half-life of 10 to 16 hours, and predominantly urinary elimination (93.8% of a radiolabeled dose); the compound does not inhibit or induce CYP3A4 in vivo. Preclinical pharmacology demonstrates antidepressant-like activity in the tail suspension test (1 mg/kg, dependent on PI3K/Akt/mTOR/GSK3-beta signaling), reversal of chronic unpredictable mild stress-induced behavioral and neurometabolic deficits, and neuroprotection comparable to MK-801 in the intrastriatal malonate model without the behavioral side effects of high-trapping NMDA antagonists. The compound is positioned within a comparator landscape that includes esketamine (approved), dextromethorphan/bupropion (approved), rapastinel (Phase 3 failed), memantine (failed for depression), and rislenemdaz (pilot only). Lanicemine is not approved for any indication. It is available as a research-grade compound for in vitro and in vivo investigation; investigators should obtain analytical confirmation of identity and purity on every lot.