What is Sunifiram?
Sunifiram (DM-235) is an ampakine drug that has the primary effect of modifying AMPA (2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid) receptor activity. It is a structural derivative of piracetam, but is 4 orders of magnitude more potent (i.e., 1000 times more powerful than oxiracetam, nefiracetam, or aniracetam). Sunifiram and a related compound (unifiram or DM-232) have chemical structures similar to the racetams and also share some of their pharmacological profile, namely an effect on cognition.
The first published article regarding its synthesis was in 2002, and most of the work concerning the compound has been done by an Italian research group (all scientific publications specifically written about sunifiram are cited in the bibliography). A limited number of studies have looked at the effects of these compounds in animal models, but none have been performed in humans.
How does it work?
The specific mechanisms of sunifiram and related compounds are not well elucidated. This is one of the reasons that clinical studies have not been performed yet. Animal work is still ongoing to further understanding of how sunifiram works.
It has been shown to prevent amnestic symptoms in rats by modulating several neurotransmission symptoms. Like other racetams, it increases acetylcholine release in the cortex; an injection of the compound doubled the concentration of acetylcholine in the central nervous system after 45 minutes. This effect does not occur via binding of acetylcholine receptors, and the mechanism is not well understood.
Sunifiram is unique in that is seems to directly influence (enhance) AMPA receptor activity, which facilitates NMDA receptor activity. Both receptor subtypes bind glutamate, but the latter is necessary to effectively encode and retrieve memories. Although sunifiram enhances receptor activity, this effect is not due to direct binding of the compound to the receptor.
In adipocytes, sunifiram stimulates nitric oxide production. This finding has not been shown in neurons, but it is possible than such an effect could increase blood flow in the central nervous system.
It is important to emphasize that the benefits to humans are theoretical because extensive clinical trials have not been done. Putatively, they would be similar to those elicited by the racetam family of compounds, but achievable with lower doses. Sunifiram is considered to have nootropic effects, meaning it may facilitate attention and the acquisition, storage and retrieval of information. It has also been shown to have analgesic effects and can increase pain threshold in a dose-dependent manner. Sunifiram may also be useful in treating seizures and seems to inhibit glucose support at high doses.
Sunifiram Side Effects
Clinical human trials have not been conducted, so we know virtually nothing about possible side effects or toxicity in people. However, a dose 1000 times greater than the highest effective doses did not affect motor coordination or spontaneous movement in animal models.
As mentioned above, this compound is relatively new and the pharmacokinetics of sunifiram in humans are not known. The effective oral dose range tested in animals was 0.01-1.0 mg/kg, which would be comparable to 0.7-7 mg per day for an average sized adult (70 kg or 154 lb).
Galeotti, N., C. Ghelardini, A. Pittaluga, A. M. Pugliese, A. Bartolini, D. Manetti, M. N. Romanelli, and F. Gualtieri. “AMPA-receptor Activation Is Involved in the Antiamnesic Effect of DM-232 (unifiram) and DM-235 (sunifiram).” Naunyn-Schmiedeberg’s Archives of Pharmacology 368.6 (2003): 538-45. Print.
Ghelardini C., Galeotti N., Gualtieri F., Romanelli M., Bucherelli C., Baldi E., and Bartolini A. “DM235 (sunifiram): a Novel Nootropic with Potential as a Cognitive Enhancer.” Naunyn-Schmiedeberg’s Archives of Pharmacology 365.6 (2002): 419-26. Print.
Martini, Elisabetta, Monica Norcini, Carla Ghelardini, Dina Manetti, Silvia Dei, Luca Guandalini, Michele Melchiorre, Simona Pagella, Serena Scapecchi, Elisabetta Teodori, and Maria Novella Romanelli. “Design, Synthesis and Preliminary Pharmacological Evaluation of New Analogues of DM232 (unifiram) and DM235 (sunifiram) as Cognition Modulators.” Bioorganic & Medicinal Chemistry 16.23 (2008): 10034-0042. Print.
Martini, Elisabetta, Carla Ghelardini, Silvia Dei, Luca Guandalini, Dina Manetti, Michele Melchiorre, Monica Norcini, Serena Scapecchi, Elisabetta Teodori, and Maria Novella Romanelli. “Design, Synthesis and Preliminary Pharmacological Evaluation of New Piperidine and Piperazine Derivatives as Cognition-enhancers.” Bioorganic & Medicinal Chemistry 16.3 (2008): 1431-443. Print.
Martini, Elisabetta, Alberto Salvicchi, Carla Ghelardini, Dina Manetti, Silvia Dei, Luca Guandalini, Cecilia Martelli, Michele Melchiorre, Cristina Cellai, Serena Scapecchi, Elisabetta Teodori, and Maria Novella Romanelli. “Design, Synthesis and Nootropic Activity of New Analogues of Sunifiram and Sapunifiram, Two Potent Cognition-enhancers.” Bioorganic & Medicinal Chemistry 17.21 (2009): 7606-614. Print.
Romanelli, M. N., N. Galeotti, C. Ghelardini, D. Manetti, E. Martini, and F. Gualtieri. “Pharmacological Characterization of DM232 (Unifiram) and DM235 (Sunifiram), New Potent Cognition Enhancers.” CNS Drug Reviews 12.1 (2006): 39-52. Print.
Scapecchi, Serena, Elisabetta Martini, Dina Manetti, Carla Ghelardini, Cecilia Martelli, Silvia Dei, Nicoletta Galeotti, Luca Guandalini, Maria Novella Romanelli, and Elisabetta Teodori. “Structure–activity Relationship Studies on Unifiram (DM232) and Sunifiram (DM235), Two Novel and Potent Cognition Enhancing Drugs.” Bioorganic & Medicinal Chemistry 12.1 (2004): 71-85. Print.
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