Unifiram, ≥99%

Chemical Information:

Technical Information:

Background:

Unifiram (DM-232) is structurally similar to Sunifiram, and is a highly potent AMPAkine-line compound with effective cognition-enhancing and anti-amnesiac effects in animal models. Although sometimes grouped with racetam compounds, Unifiram is technically not a racetam due to the broken pyrrolidone backbone. [1]

Animal research has shown that Unifiram has a significantly greater Nootropic potency than Piracetam or Phenylpiracetam. Unifiram is shares structural similarities to Sunifiram. Animal models show similar modes of action for both compounds – increased cognitive performance and anti-amnesiac effects through interactions with the glutamatergic system and particularly through AMPA-receptor activation. [2]

Unifiram is a novel and exciting research chemical in the fields of neuroscience and the study of biochemical pathways and glutamatergic mechanisms. However, there is a need for further research on the toxicology and pharmacokinetics of this compound. It is important to emphasize that, until these studies are completed, Unifiram should be treated as a potentially hazardous research compound.

In 2006, researchers studied the pharmacological characterization of both Sunifiram and Unifiram, finding that both compounds were an order of four magnitudes more potent than Pircatem. Unifiram, they found, is able to prevent amnesia through the modulation of several neurotransmitter systems. [3]

Modes of action:

Although the Unifiram did not show any affinity for several important binding sites, it was found to prevent amnesia through modulation of various neurotransmitter systems and by increasing acetylcholine release in the cerebral cortex.

At a concentration of 1 uM, both Sunifiram and Unifiram did not shown any affinity towards muscarinic and nicotinic receptors, nor for the most important central receptors. The authors found that Unifiram produced lost lasting increases in neurotransmission in the CA1 region of rat hippocampal slices in a concentration-dependent and irreversible manner. [3]

The lack of an affinity towards central receptors is a characteristic feature of many Nootropics compounds, which generally do not show affinity for many of the most common receptor systems. [4]  

The authors further hypothesized that Unifiram may enhance the release of putative neurotransmitters like glutamate or increase the response to glutamate at postsynaptic levels on AMPA receptors – as has been shown for Sunifiram. [3]

Both Sunifiram and Unifiram were able to reverse the impairment of memory induced by the NBQX (AMPA antagonist) in the passive avoidance animal model (providing further evidence of interactions with AMPA-receptors). Further in vitro experiments on rat hippocampal slices provided more evidence to support this theory. The authors proposed that Unifiram may incluence AMPA-regulated release of secondary neurotransmitters other than norepinephrine, which may further facilitate NMDA receptor functions. [3]

Unifiram’s mechanism of action is known to be similar to that of Sunifiram. Sunifiram’s mechanism of action is better defined than that of Unifiram, and we will briefly explain it here. 

At a dosage range of 10-100nM, Sunifiram enhances NMDA-dependent signaling by increasing PKCα phosphorylation – dependent on glycine binding site availability and as an antagonist to glycine. [5]  The observable increase in AMPA receptor activation activity post-administration has been associated with increases in CAMKII and PKCα phosphorylation. Furthermore, the increased activity of AMPA receptor activation has been associated with increased CAMKII and PKCα phosphorylation [6]

Further Scientific research:

There is still a need for further scientific research into the effects and biochemical mechanisms of Unifiram, 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 available for Unifiram at this time.

Human studies:

As of 2017, no studies or clinical trials have been conducted to explore the potential effects of Unifiram in human subjects.

Toxicology studies:

No toxicology studies have been performed on Unifiram to-date (August, 2017). It is important to treat Unifiram as an experimental research chemical with potentially hazardous properties.

Animal studies:

A recent paper, published in 2016, reported on the development and patenting of Unifiram and Sunifiram. The paper summarized key findings from various animal studies on Unifiram to-date. These are outlined below: 

1. Both Uniifram and Sunifiram prevented memory loss produced by scopolamine, mecamylamine (a nicotinic antagonist), baclofen, clonidine, and NBQX. These data indicate that Unifiram has anti-amnesiac effects through interactions with neurotransmitter systems including muscarinic, nicotinic, GABAergic, alpha-2, and AMPAkine systems. [7]
2. At a dosage as low as 0.001mg/kg i.p., Unifiram was able to prevent amnesiac effects of scopolamine (in the rat Morris water test). At higher doses it had a precognitive effect - even on animals not treated with scopolamine. [8]
3. At a dosage of 0.1mg/kg, both Unifiram and Sunifiram were active in the rat social-learning test [9], and significantly reduced sleeping time induced by pentobarbital in mice.[10] 
4. Both Unifiram and Sunifiram increased the release of Acetylcholine in the rat parietal cortex and also showed analgesic effects on hot plate tests. [9]
5. Unifiram’s Nootropic effects were pronounced but did not modify the animal’s gross behavior or motor coordination. Spontaneous motility and the inspection activity were unmodified by both compounds.
6. Testing for both Unifiram and Sunifiram in the NIMH Psychoactive Drug Screening Program by the lab of Dr Brian Roth did not show any affinity for the most common CNS transporters, channels, or receptors.
7.  Results of NBQX administration in kynurenate tests indicate that AMPA receptors are involved in the anti-amnesiac effects for both Unifiram and Sunifiram.

The authors further suggest that Unifiram and Sunifiram possess a potency of up to 30’000 times higher than Piracetam, and 1’000 times higher than piracetam-like drugs like oxiracetam, nefiracetam, etiracetam, and Aniracetam. [11]

References:

• [1] Unifiram. Compound Summary for CID 9861054. (2018). PubChem: Open Chemistry Database, US National Library of Medicine [online]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/9861054 [Accessed July 19, 2018]
• [2] Martini E, Ghelardini C, Bertucci C, Dei S, Gualtieri F, Guandalini L, Manetti D, Scapecchi S, Teodori E, Romanelli MN. (2005). Enantioselective synthesis and preliminary pharmacological evaluation of the enantiomers of unifiram (DM232), a potent cognition-enhancing agent. Med Chem, 1:473–480.
• [3] Romanelli MN, 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: 39–52.
• [4] Gouliaev AH, Senning A. (1994). Piracetam and other structurally related nootropics. Brain Res Rev, 19:180–222
• [5] 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.
• [6] 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.
• [7] Ghelardini C, Galeotti N, Gualtieri F, Manetti D, Bucherelli C, Baldi E, Bartolini A. (2002). The novel nootropic compound DM232 (UNIFIRAM) ameliorates memory impairment in mice and rats. Drug Dev Res, 56:23–32
• [8] Martini E, Ghelardini C, Dei S, Guandalini L, Manetti D, Melchiorre M, Norcini M, Scapecchi S, Teodori E, Romanelli MN. (2008). Design synthesis and preliminare pharmacological evaluation of new analogues of DM232 (unifiram) and DM235 (sunifiram) as cognition modulator. Bioorg Med Chem, 16:10034–47
• [9] 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, 365:419–26
• [10] 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, 43:4499–507
• [11] Gualtieri F. (2016) Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings. Journal of Enzyme Inhibition and Medicinal Chemistry, 1(2): 187-94.