Sunifiram (DM235) powder (314728-85-3)

Sunifiram (DM-235) powder 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.

Sunifiram (DM-235) powder 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.

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.

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.

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.

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.

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.

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). 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).

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.

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.

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.

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.

COA

[1] Romanelli M, Galeotti N, Ghelardini C, Manetti D, Martini E, Gualtieri F. (2006). Pharmacological characterization of DM232 (unifiram) and DM235 (sunifiram), new potent cognition enhancers. CNS Drug Reviews, 12 (1): 39–52.

[2] Moriguchi S, Tanaka T, Narahashi T, Fukunaga K. (2013). Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine binding site of N-methyl-D-aspartate receptor. Hippocampus, 23(10):942-51.

[3] Moriguchi S, Tanaka T, Tagashira H, Narahashi T, Fukunaga K. (2013) Novel nootropic drug sunifiram improves cognitive deficits via CaM kinase II and protein kinase C activation in olfactory bulbectomized mice. Behav Brain Res, 242:150-7.

[4] Manetti D,  Ghelardini C, Bartolini A, Dei S, Galeotti N, Gualtieri F, Romanelli MN, Teodori E. (2000) Molecular simplification of 1,4-diazabicyclo{4.3.0}nonan-9-ones gives piperazine derivatives that maintain high nootropic activity. J Med Chem, 43(23):4499-507.

[5] Galeotti N, Ghelardini C, Pittaluga A, Pugliese AM, Bartolini A, Manetti D, Romanelli MN, Gualtieri F. (2003). AMPA-receptor activation is involved in the antiamnesic effect of DM232 (unifiram) and DM235 (sunifiram). Naunyn Schmiedeberg’s Arch Pharmacol, 368:538–545.

[6] Ghelardini C, Galeotti N, Gualtieri F, Romanelli MN, Bucherelli C, Baldi E, Bartolini A. (2002). DM235 (Sunifiram): A novel nootropic with potential as cognitive enhancer. Naunyn-Schmiedeberg’s Arch Pharmacol, 365:419–426.