Amandatine

It seems likely that Amantadine acts as a PDE1 inhibitor, which may increase cyclic AMP levels and contribute to its neuroprotective effects.
Studies indicate Amantadine increases AADC expression, enhancing dopamine synthesis from L-DOPA, which is crucial for its antiparkinsonian effects.
Amantadine is known to block dopamine reuptake, increasing extracellular dopamine levels, which helps in managing Parkinson’s symptoms.
The evidence leans toward Amantadine indirectly interacting with D2 receptors by raising dopamine levels, though it doesn’t directly bind to them, affecting receptor activity.
Research suggests Amantadine stimulates noradrenergic responses, potentially enhancing noradrenaline release, which may contribute to its effects on mood and fatigue.
It appears Amantadine has immunomodulatory effects, reducing T lymphocytes and altering cytokine levels, which could be relevant in conditions like multiple sclerosis.
Beyond the listed terms, Amantadine also shows effects like NMDA receptor antagonism, acting as a sigma-1 receptor agonist, and modulating nicotinic acetylcholine receptors, among others, expanding its therapeutic potential.
Amantadine is identified as a phosphodiesterase inhibitor, particularly affecting PDE1, with an IC50 of approximately 5 μM, potentially increasing cyclic AMP levels. This action may contribute to its neuroprotective and anti-inflammatory properties, as noted in studies like Kakkar et al. (1997) and Sancesario et al. (2014). This effect is significant in neurological conditions, where PDE1 inhibition can modulate cAMP signaling, potentially reducing levodopa-induced dyskinesias.
Research, including a 1998 study by Hsu et al., demonstrates that Amantadine increases AADC mRNA in PC12 cells at concentrations of 10 and 100 μM, enhancing the enzyme’s activity by up to 27% in human striatum imaging studies. This increase is crucial for dopamine synthesis from L-DOPA, supporting its role in Parkinson’s disease therapy, as seen in studies like those by UCL Discovery.
Amantadine’s ability to block dopamine reuptake is well-documented, with studies showing it increases extracellular dopamine levels in the striatum, an effect attenuated by coadministration of nomifensine, a known dopamine reuptake inhibitor. This action, detailed in research by Mizoguchi et al. (1994), enhances dopaminergic neurotransmission, aiding in symptom management for Parkinson’s and depression-like conditions.
While Amantadine does not directly bind to D2 receptors, it indirectly interacts with them by increasing dopamine levels, which can enhance D2 receptor activity. This is supported by studies like Moresco et al. (2002), which observed increased [11C-]raclopride binding, indicating higher D2 receptor availability, likely due to elevated dopamine. This indirect effect is part of its dopaminergic actions, as noted in Wikipedia and ScienceDirect overviews.
Amantadine’s noradrenergic effects include stimulating norepinephrine release, as evidenced by studies like Farnebo et al. (1971), which suggest it enhances noradrenergic transmission. This action is part of its broader neurotransmitter modulation, potentially contributing to its antidepressant and fatigue-reducing effects in conditions like multiple sclerosis, as seen in reviews by PMC.
Amantadine exhibits immunomodulatory effects, reducing T lymphocytes and altering cytokine levels (e.g., IL-2, TNF, IFN-γ), as shown in studies on multiple sclerosis patients by Clark et al. (1989) and Wandinger et al. (1999). This action is particularly relevant in neuroinflammatory conditions, with evidence from ScienceDirect indicating its anti-inflammatory function.
NMDA Receptor Antagonism: Amantadine acts as a weak, non-competitive NMDA receptor antagonist, stabilizing channel closure and reducing glutamatergic excitotoxicity, as detailed in Blanpied et al. (2005).
Sigma-1 Receptor Agonist: It binds to and activates sigma-1 receptors, potentially contributing to neuroprotection, as noted in DrugBank and Wikipedia overviews.
Nicotinic Acetylcholine Receptor Negative Allosteric Modulator: Amantadine modulates nicotinic acetylcholine receptors, affecting cholinergic signaling, which may play a role in its side effect profile and therapeutic actions.
Induction of GDNF Expression: Studies like Caumont et al. (2006) report that Amantadine induces glial-derived neurotrophic factor (GDNF) expression in astroglia, supporting neuronal survival and potentially aiding in neurodegenerative disease management.
Antiviral Action: Its inhibition of the M2 proton channel of influenza A virus prevents viral replication, though resistance has limited its use, as noted in MedlinePlus.
Possible Weak 5-HT3 Receptor Antagonist: Some research suggests weak antagonistic effects at 5-HT3 receptors, potentially contributing to its effects on nausea and mood, though this is less studied.
Blockade of Certain Ion Channels: Amantadine blocks ion channels like those encoded by SARS-CoV-2 (e.g., Protein E, ORF10), and studies on viral potassium channels suggest it affects channel function, as seen in PMC articles.

Action	Description	Relevance
PDE1 Inhibition	Inhibits PDE1, increasing cAMP levels, potentially neuroprotective.	Neurological conditions, anti-inflammatory.
AADC Expression Increase	Enhances AADC activity, boosting dopamine synthesis from L-DOPA.	Parkinson’s disease therapy.
Dopamine Reuptake Inhibition	Blocks dopamine reuptake, increasing extracellular dopamine.	Antiparkinsonian, antidepressant effects.
D2 Receptor Interactions (Indirect)	Increases dopamine, indirectly affecting D2 receptor activity.	Dopaminergic modulation.
Noradrenergic Actions	Stimulates norepinephrine release, enhancing noradrenergic transmission.	Mood, fatigue management.
Immunomodulation	Reduces T lymphocytes, alters cytokines, anti-inflammatory.	Neuroinflammatory conditions.
NMDA Receptor Antagonism	Weak non-competitive antagonist, reduces glutamatergic excitotoxicity.	Neuroprotection, antiparkinsonian.
Sigma-1 Receptor Agonist	Activates sigma-1 receptors, potentially neuroprotective.	Neuroprotection.
Nicotinic ACh Receptor Modulator	Negative allosteric modulator, affects cholinergic signaling.	Side effect profile, therapeutic actions.
GDNF Induction	Induces GDNF expression in astroglia, supports neuronal survival.	Neurodegenerative disease support.
Antiviral Action	Blocks M2 proton channel, inhibits influenza A replication (resistance noted).	Historical antiviral use.
Weak 5-HT3 Receptor Antagonist	Possible weak antagonism, may affect nausea and mood.	Less studied, potential side effects.
Ion Channel Blockade	Blocks certain viral and potassium channels, affects channel function.	Antiviral, potential neurological effects.