Amantadine

Amantadine (CAS No.: 768-94-5) is a multi-target tricyclic amine small molecule that acts primarily by blocking viral ion channels and modulating multiple neurotransmitter/receptor pathways. It can serve as a blocker of the influenza A virus M2 proton channel and the SARS-CoV-2 E protein viroporin, inhibiting viral uncoating and replication, and shows significant inhibitory activity against BoDV-1 replication. In the central nervous system, Amantadine is an open-channel blocker of α4β2 and α7 nAChRs (IC₅₀ approximately 3.44 μM and 6.5 μM, respectively), a 5‑HT₃ receptor antagonist (IC₅₀≈21.1–31.5 μM), a low-affinity noncompetitive NMDA receptor antagonist (IC₅₀≈12.4–165 μM, with reduced effects under physiological Mg²⁺ conditions), and can block Kir2 inwardly rectifying potassium channels (IC₅₀≈27 μM). At the intracellular level, it inhibits calmodulin-dependent PDE1 (IC₅₀≈5 μM), reduces cAMP/cGMP degradation, upregulates AADC expression and activity, promotes GDNF release (EC₅₀≈6.2 μM), and, as a high-affinity σ‑1 receptor ligand, regulates intracellular Ca²⁺ signaling, collectively affecting dopaminergic neurotransmission, glutamate excitotoxicity, second messenger pathways, and neurotrophic factor/neuroinflammation-related pathways.

In cellular studies, Amantadine is mainly used in PC12 cells, C6 glioma cells, primary neurons and microglia, and cell lines transfected with specific receptors, with dosing concentrations ranging from nanomolar to millimolar levels, to evaluate effects such as inhibition of BoDV‑1 and SARS‑CoV‑2 replication (ID₅₀ for BoDV‑1≈0.025 μM, significantly stronger than memantine; in vitro ID₅₀ for SARS‑CoV‑2 approximately 83–119 μM, higher than clinically achievable exposure levels), receptor blockade, electrophysiological properties, PDE1 inhibition and cAMP/cGMP dynamics, AADC expression upregulation, and GDNF secretion. In protein glycoxidation models, high-concentration Amantadine (approximately 1 mM) shows only moderate scavenging capacity toward hydroxyl radicals and hydrogen peroxide (scavenging rate approximately 50–70%), and overall lacks clear anti-protein glycation activity; under some conditions it even displays pro-glycoxidative or pro-oxidative effects, suggesting that its neuroprotection is mainly not achieved through direct antioxidation.

In animal experiments, Amantadine is mainly used for therapeutic intervention in various neurological disease models. Common dosing regimens include oral administration of 25–100 mg/kg in rat Parkinson’s disease models, intraperitoneal injection of 5–135 mg/kg in traumatic brain injury models, approximately 45–100 mg/kg/day in experimental autoimmune encephalomyelitis and spinal cord injury models, and 20–100 mg/kg in cerebral ischemia and depression models, to assess endpoints such as improvement of motor symptoms, neuroprotection and anti-apoptosis, regulation of inflammatory responses, and antidepressant effects and cognitive functional recovery. Most studies suggest that Amantadine can improve motor function, reduce neuroinflammation, and promote axonal/synaptic remodeling to a certain extent, consistent with its combined effects on dopaminergic regulation, NMDA receptors, and the σ‑1/GDNF pathway.

At the clinical level, Amantadine has been approved for the prevention and treatment of influenza A, as well as as adjunctive medication for Parkinson’s disease and levodopa-induced dyskinesia. Pharmacokinetic studies show that oral administration of 200 mg/day produces a steady-state plasma concentration of approximately 5 μM, while at 600 mg/day the Cmax is approximately 14.6 μM; cerebrospinal fluid concentrations are approximately 76% of plasma levels, and the compound can accumulate in lysosomes, allowing intracellular concentrations to reach 10–20 times plasma levels. Clinical studies support exploration of its efficacy in multiple sclerosis-related fatigue (100 mg bid), recovery of consciousness and cognition after traumatic brain injury (approximately 200 mg/day), Huntington’s disease chorea, and tardive dyskinesia; for BoDV-associated depression, a dose of approximately 200 mg/day has shown both antiviral and antidepressant effects with good tolerability in case/small-sample studies. In addition, multiple trials are still evaluating its potential applications in indications such as depression, spinal cord injury rehabilitation, neuropathic pain, epilepsy, and antipsychotic-associated weight gain.

References:

[1] Danysz W, Dekundy A, Scheschonka A, Riederer P. Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials. J Neural Transm (Vienna). 2021 Feb;128(2):127-169. doi: 10.1007/s00702-021-02306-2. Epub 2021 Feb 23. PMID: 33624170; PMCID: PMC7901515.

[2] Bode L, Dietrich DE, Spannhuth CW, Ludwig H. Prominent Efficacy of Amantadine against Human Borna Disease Virus Infection In Vitro and In Vivo. Comment on Fink et al. Amantadine Inhibits SARS-CoV-2 In Vitro. Viruses 2021, 13, 539. Viruses. 2022 Feb 28;14(3):494. doi: 10.3390/v14030494. PMID: 35336901; PMCID: PMC8953669.

[3] Nesterowicz M, Żendzian-Piotrowska M, Ładny JR, Zalewska A, Maciejczyk M. Antiglycoxidative properties of amantadine - a systematic review and comprehensive in vitro study. J Enzyme Inhib Med Chem. 2023 Dec;38(1):138-155. doi: 10.1080/14756366.2022.2137161. PMID: 36325591; PMCID: PMC9639497.