DM-235, 1-benzoyl-4-propanoylpiperazine, 314728-8503 (CAS Number), CID 4223182 (PubChem), CHEMBL309176, C14H18N2O2
Structurally related to Piracetam, Sunifiram is a relatively new entrant in the field of Nootropics (first studies published in 2000) that has shown a considerably higher potency than Piracetam in the animal studies that have been conducted thus far. The early animal studies that have been conducted point to Sunifiram being an anti-amnesiac and general cognitive aid.
Sunifiram’s Mechanism of Action
Preliminary studies suggest Sunifiram has two main mechanisms of action:
Sunifiram is structurally similar to that of other ampakines; its main mechanism of action is as an agonist of AMPA receptors. In mouse studies, the subjects were given an AMPA antagonist known as NBQX, and after being treated with Sunifiram, showed a reversal of the effects of NBQX. Sunifiram, as an AMPA agonist, could also show promise in the areas of memory and learning improvement, as well as increasing attention span and alertness, but no such experiments have been conducted yet to confirm or deny these effects.
As well as being an ampakine, one study has shown Sunifiram to aid in the release of acetylcholine in the cerebral cortex, in rat studies. As a Cholinergic compound, Sunifiram could be involved in improved decision making, better ability to convert short-term memory to long-term memory, and aid in motor skills through the increased control over muscle contraction. More studies would need to be conducted to validate these possible effects.
The majority of studies that have been conducted on Sunifiram so far point to its anti-amnesic effect, and its implications in the treatment of Alzheimer’s, in comparison to other drugs in the Racetam category. In comparison, with Piracetam being the most well-known of the Racetams, Sunifiram is noted to be roughly 1000 time more potent than Piracetam (by weight).
One such study induced amnesia in mice by administering scopolamine, mecamylamine, baclofen, and clonidine; after administering the amnesia-inducing drugs, the mice were put through the Morris Water Maze test. While under the influence of the amnesiacs, the mice were tested on their ability to escape the maze; the mice were then tested on the Morris Water Maze after given various doses of Sunifiram. The experimenters found the Sunifiram-treated mice experienced significantly less amnesic effects from the Scopolamine, which was quantified through measurement of their escape latency scores. The researchers concluded that Sunifiram appears to be highly-effective at preventing cognitive decline, but were unable to determine how Sunifiram may effect otherwise healthy individuals, due to the nature of the study.
Another study used olfactory bulbectomized mice to test what effect Sunifiram has on both memory impairment and depression. For the memory impairment portion of the experiment, mice that had been treated with Sunifiram were subjected to the Y-Maze test and Novel Object Recognition test, and their scores on each respective test were compared with those of mice who had not been treated with Sunifiram. The researchers found the mice that had been treated with Sunifiram for a period of time performed significantly better than the olfactory bulbectomized mice who had not received the drug. For the purposes of testing the effects of Sunifiram on depression, the both the control group and experimental group of olfactory bulbectomized mice were subjected to the Tail Suspension task; the researchers concluded there was no significant difference between the two groups on this task. During the course of their research, there were a few interesting neurochemical changes noted: the phosphorylation of CaMKIIα, GluR1, PKCα, and NR1 returned to control levels in the olfactory bulbectomized mice while on Sunifiram; all of these have been implicated in various processes related to memory and learning.
In the mouse studies that have been conducted, the researchers used an oral administration of (0.01-0.1 mg kg(-1) in mice, which (after using allometric scaling) converts to ~.09mg/kg in humans, or roughly 6mg for a 150lb person.
The published animal studies have shown no short-term toxicity at the investigated doses of .01-.1mg/kg in mice.
- Galeotti N, Ghelardini C, Pittaluga A, Pugliese AM, Bartolini A, Manetti D, Romanelli MN, Gualtieri F. AMPA-receptor activation is involved in the antiamnesic effect of DM 232 (unifiram) and DM 235 (sunifiram). Department of Preclinical and Clinical Pharmacology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
- Elisabetta Martini, Carla Ghelardini, Monica Norcini, Dina Manetti, Silvia Dei, Luca, Guandalini, Michele Melchiorre, Serena Scapecchi, Elisabetta Teodori, Fulvio Gualtieri, Maria Novella Romanelli. Design, synthesis and preliminary pharmacological evaluation of new analogues of DM232 (unifiram) and DM235 (sunifiram) as cognition modulators. Dipartimento di Scienze Farmaceutiche, Università di Firenze, via Ugo Schiff 6, 50019. Sesto Fiorentino, Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, viale Pieraccini 6, 50139 Firenze. Presenting author: firstname.lastname@example.org
- Dina Manetti, Carla Ghelardini, Alessandro Bartolini, Silvia Dei, Nicoletta Galeotti, Fulvio Gualtieri, Maria Novella Romanelli, and Elisabetta Teodori. Molecular Simplification of 1,4-Diazabicyclo[4.3.0]nonan-9-ones Gives Piperazine Derivatives That Maintain High Nootropic Activity. Dipartimento di Scienze Farmaceutiche, Universita` di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy, and Dipartimento di Farmacologia Preclinica e Clinica, Universita` di Firenze, Viale Pieraccini 6, I-50139 Firenze, Italy.
- Ghelardini C, Galeotti N, Gualtieri F, Romanelli MN, Bucherelli C, Baldi E, Bartolini A. DM235 (Sunifiram): A Novel Nootropic with potential as a cognitive enhancer. Naunyn-Schmiedeberg’s Arch Pharmacol (2002) 365: 419-426. DOI 10.1007/s00210-002-0577-3.
- Moriguchi S, Tanaka T, Tagashira H, Narahashi T, Fukunaga K. Novel nootropic drug sunifiram improves cognitive deficits via CaM kinase II and protein kinase C activation in olfactory bulbectomized mice. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. Behav Brain Res. 2013 Apr 1;242:150-7. doi: 10.1016/j.bbr.2012.12.054. Epub 2013 Jan 4.
- M. N. Romanellia, N. Galeottib, C. Ghelardini, D. Manettia, E. Martinia, F. Gualtieri. Pharmacological Characterization of DM232 (Unifiram) and DM235 (Sunifiram), New Potent Cognition Enhancers. aDipartimento di Scienze Farmaceutiche, University of Florence, Sesto Fiorentino, Italy; bDipartimento di Farmacologia Preclinica e Clinica, University of Florence, Firenze, Italy. CNS Drug Reviews Vol. 12, No. 1, pp. 39–52.