Sunifiram, ≥99%

Chemical Information:

Technical Information:

Background:

Sunifiram (DM-235) is an experimental research chemical derived from Piperazine that has potent anti-amnesia effects. It is often grouped with the racetam compounds but is technically not a racetam due to the broken pyrrolidone backbone.[1] 

Animal research has shown that it has a significantly greater potency than Piracetam or Phenylpiracetam. Sunifiram is related to Unifiram – it is a chemically simplified version of Unifram. Animal studies indicate that one key mode of action for Sunifiram is through interactions with the glutamergic system – particularly through AMPA-receptor activation. It is therefore considered an AMPAkine. [2] 

Sunifram is still a highly experimental chemical and has not yet been subjected to any human clinical trials or toxicology studies. It is therefore important to note the potentially hazardous nature of this compound to less experienced researchers. Sunifiram is not approved for pharmaceutical sale in any country.   

In 2006, researchers indicated that both Sunifiram and Unifiram were around four orders of magnitude more potent than Piracetam. Although the compounds did not show affinity for several important binding sites, they were found to prevent amnesia through modulation of various neurotransmitter systems and by increasing acetylcholine release in the cerebral cortex. [3]

Modes of action:

Sunifiram enhances NMDA-dependent signaling by increasing PKCα phosphorylation, at a dosage range of 10-100nM. This mechanism of action is dependent on the availability of the glycine binding site and Sunifiram has been shown to act as an antagonist to glycine at a concentration of 300μM.[4]

Furthermore, the increased activity of AMPA receptor activation has been associated with increased CAMKII and PKCα phosphorylation. Although studies have confirmed that intracellular proteins like CAMKII and PKCα are activated after Sunifiram administration, other proteins like CaMKIV and ERK remain unaffected. [5]

A brief summary of the mechanism of action, as it is currently understood, is that Sunifiram acts on the NMDA receptor’s glycine binding site, which results in increased signaling and activation of CAMKII and PKCα proteins and the subsequent positive regulation of AMPA receptors.

Furthermore, animal studies have indicated that a dosage of 0.01mg/kg increases acetylcholine release by up to 200% within one hour of injection, in rat prefrontal cortex. This effect is not seen at a higher dosage of 1mg/kg. [6]

Further Scientific research:

The is still a need for further scientific research into the effects and mechanisms of Sunifiram, especially in human subjects. No human clinical studies have been published as yet, and Sunifiram is not approved for pharmaceutical sale in any country.

Clinical Reviews:

Due to the lack of published data, there are no reviews or meta-analyses on Sunifiram available, as of August 2017.

Human studies: 

No human clinical studies have been conducted to investigate the effects and/or toxicological profile of Sunifiram.

Toxicology studies:

No toxicology studies have been performed using human subjects.

One study found that the minimum effective dosage for Sunifiram was as low as 0.001mg/kg, and the authors failed to find any toxic effects, even at dosages 1000-fold higher (1mg/kg). [7] 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).[4]

Animal studies: 

Animal studies show that Sunifiram has the ability to enhance long-term potentiation (LTP) in a highly efficient manner. In vivo studies, at a dosage range of 0.01-1mg/kg for 7-12 days, show that Sunifiram’s effects are initially dependent on the glycine binding site at NMDA receptors and subsequently increase AMPA receptor activity. [6] Further animal studies have shown that a dosage of 1mg/kg has the ability to prevent memory reductions after training sessions in mice with hippocampal memory impairments. Furthermore, Sunifiram was able to improve long-term potentiation in these animals. [6]

Studies have shown that both Unifiram and Sunifiram (structurally related to AMPAkines) have the potential to reduce amnesia induced by AMPA receptor antagonist NBQX (30mg/kg i.p.), in the mouse passive avoidance test. The Nootropic compounds did not impair motor coordination, motility, or inspection activity. Furthermore, both compounds reversed kynurenic acid antagonism at NMDA-mediated [(3)H]NA release in rat hippocampal slices. [7]

Another key finding is that Sunifiram administration at a minimal dosage of 0.01mg/kg – for both i.p. and p.o. – helps to prevent amnesia caused by scopolamine in mouse passive avoidance tests. This anti-amnesiac capability has a potency around 1,000 to 10,000 fold stronger than that of well-known Nootropic drugs like Piracetam (30mg/kg i.p.), Aniracetam (100mg/kg p.o.) and Rolipram (30mg/kg p.o.). [8]

Animal studies have not shown any anti-depressive effects. For example, an animal study on olfactory bulbectomized mice found that 0.1-1mg/kg dosages of Sunifiram did not reduce symptoms of depression. [5]

References: