Summary of Sunifiram
Primary Information, Benefits, Effects, and Important Facts
Sunifiram (DM-235) is a synthetic derivative of piracetam, although due to breaking the pyrrolidone backbone it is no longer in the racetam class of drugs (yet by being derived from them, it is still commonly associated with this class).
Sunifiram has mechanisms similar to nefiracetam in the hippocampus, and similar to that drug sunifiram shows anti-amnesiac properties and is potentially a cognitive enhancer. Its anti-amnesiac activity is several orders of magnitude greater than piracetam on a per weight basis, and preliminary evidence suggest it has a similarly low toxicity profile.
This compound is known as an AMPAkine due to exerting most of its actions via the AMPA receptor (one of the three main subsets of glutamate receptors, alongside NDMA and kainate). This enhancement of AMPA function seems to also rely on enhancing signalling via the glycine binding site of NMDA receptors, although one minimal signalling goes through the NMDA receptor then the benefits on AMPA receptors seem dose-dependent.
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Sunifiram (DM-235) is a nootropic drug that is commonly associated with the racetam drugs (although it itself is not a racetam) as it is a pyrrolidone derivative. Sunifiram is structurally related to both unifiram (DM-232) and sapunifiram (MN-19), as all three molecules are piperazine alkaloids.
Sunifiram is reported to be four orders of magnitude more potent than Piracetam in regards to antiamnesiac potential. Injections of 0.1mg/kg appear to have cognitive enhancing properties comparable to 30mg/kg piracetam in otherwise normal adult rats.
Sunifiram is a synthetic analogue of Piracetam that, due to opening the pyrrolidinone ring (pentagon with a nitrogen) is no longer classified as a racetam compound. It still retains cognitive enhancing properties
Sunifiram is a piperazine alkaloid (referring to the hexagon with two nitrogen groups) that is derived from Piracetam. Using the related structure unifiram as an example, the sidechain of piracetam is fused into a piperazine structure by reconnecting it to the pyrrolidine backbone, and then sunifiram sees an opening of the pyrrolidine backbone (not observed in unifiram) which is known to not be vital for the cognitive enhancing properties of piracetam-like drugs.
Sunifiram is, essentially, a molecule that closed the sidechain of piracetam into a piperazine ring structure and then eliminated the typical pentagon backbone
2.1. Glutaminergic Neurotransmission
10-100nM of sunifiram has been noted to enhance NMDA-dependent signalling via an increase in PKCα phosphorylation, dependent on the glycine binding site and acting antagonistically to glycine (300μM). This receptor activation actiates Src, and inhibiting Src inhibits the increase in long term potentiation. NMDA-depedent long-term potentiation has been confirmed in vivo with 0.01-1mg/kg oral intake of sunifiram for 7-12 days.
While signalling via the NDMA receptor exhibited a bell-curve response peaking at 10nM it was able to cause concentration-dependent enhancement of neuronal signalling up to 1,000nM due to an increase in AMPA receptor phosphorylation. Increases in AMPA receptor activation was associated with an increase in (NMDA receptor dependent) CAMKII phosphorylation and PKCα both of which have been confirmed in vivo with 0.01-1mg/kg sunifiram oral ingestion and are blocked by a glycine-site NMDA antagonist. AMPA receptor activation has been noted elsewhere to be associated with the anti-amnesiac effects of sunifiram.
Sunifiram appears to act on the glycine binding site of NMDA receptors, which enhances signalling and activates some intracellular proteins (CAMKII and PKCα) which then positively regulate the AMPA receptors. These mechanisms are highly similar to that seen with nefiracetam
2.2. Cholinergic Neurotransmission
Sunifiram injections at 0.01mg/kg are able to facilitate acetylcholine release in the prefrontal cortex of rats, with no apparent efficacy at 1mg/kg. The magnitude was around 200% of baseline within an hour of injection.
Although only one study has been conducted, it appears that sunifiram may enhance acetylcholine secretion in the prefrontal cortex
2.3. Learning and Memory
Although CAMKII and PKCα (intracellular proteins downstream of NDMA receptor activation) have been confirmed to be activated in vitro and in vivo, CaMKIV and ERK are unaffected.
Sunifiram is known to enhance long-term potentiation (LTP) in vitro (10-1000nM) and in vivo (0.01-1mg/kg for 7-12 days oral intake) in a manner that is initially dependent on the NMDA receptor (particularly, the glycine binding site) but then positively influences the activity of AMPA receptors.
In olfactory bulbectomized mice with hippocampal dependent memory impairments, sunifiram at 1mg/kg is able to abolish the reductions seen when given after training sessions. LTP in these mice (normally impaired and causes memory dysfunction) was also normalized to control levels.
Amnesia induced by scopolamine, baclofen, diphenhydramine, and clonidine have all been noted to be reduced with sunifiram with injected doses as low as 0.001mg/kg and oral doses as low as 0.01mg/kg.
Appears to promote long term potentiation in the hippocampus with oral ingestion, which should result in an improvement in memory in animals that have otherwise impaired memory
One study (social learning paradigm) in otherwise normal adult rats noted that 0.1mg/kg injections of piracetam were as effective in promoting cognition as 30mg/kg piracetam as reference drug.
Limited evidence supports cognitive enhancement in otherwise healthy rodents
Depressive effects seen in olfactory bulbectomized mice are not affected by 0.1-1mg/kg of sunifiram, which may be due to the depressive effects in this research model being associated with reduced ERK activation and sunifiram not affecting ERK.
No observable anti-depressive effects
A study noting efficacy of sunifiram (0.001mg/kg denoted minimum effective dose) failed to find any overt toxic symptoms with a 1000-fold higher dose injected (1mg/kg).
Currently no known toxicity associated with Sunifiram