Two studies noted Unifiram increased the release of acetylcholine and a third study showed Unifiram negated the effects of scopolamine.
Unifiram, also known as: (8aR)-2-[(4-fluorophenyl)sulfonyl]hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one, (CAS Number) 272786-64-8, (PubChem) CID 9861054, (ChemSpider) 8036753, (ChEMBL) CHEMBL140717, C13H15FN2O3S, DM232 History Unifiram (DM-232) is another recent entrant in the Racetam family which is structurally similar to an ampakine and is closely related to Sunifiram (DM-235), with the first studies on the drug being published in 2003. More studies need to be conducted to fully elucidate the effects of Unifiram, but it appears to be effective as a Nootropic and as an anti-amnesic. Mechanism of Action Based on the studies conducted, both in vivo and in vitro, Unifiram reverses the effects of AMPA antagonists, NMDA antagonists, and muscarinic antagonists, which would imply the underlying mechanisms of action. One study found that Unifiram reversed the effects of both AMPA antagonists and NMDA antagonists, both of which mimic glutamate, and are directly correlated to learning and memory . Two studies noted that Unifiram increased the release of acetylcholine in rats, and a third study showed Unifiram negated the effects of scopolamine [3.4.6]; at first glance, these two facts may not seem to be related, but it turns out scopolamine is a muscarinic antagonist specifically affecting the M1 receptor. Reducing the effect of a muscarinic antagonist could be the explanation for the noted increase in acetylcholine release, as the M1 muscarinic receptor is a cholinergic receptor. The effect causing Unifiram to inhibit the negative effects of muscarinic antagonism is most likely the same cause for the increase in acetylcholine. Benefits In the studies conducted, Unifiram was noted to have three primary benefits: anti-amnesia, acetylcholine agonism, and anti-sedative and anti-hypnotic effects. Two of the studies on Unifiram and its analogs focused on its ability to reverse the amnesic effects of AMPA antagonists and its precognitive effects utilizing the Mouse Passive Avoidance test for their experimental methodology [1,2]. Another study noted that Unifiram appears to increase acetylcholine release in rats; acetylcholine is very strongly correlated to memory and learning . There was one other study done that found, on top of being an anti-amnesic, Unifiram reduces the effects of barbiturates especially the effects of hypnosis and sedation . Dosing In the few studies done, the most common dose was .1mg/kg in both mice and rats and was found to be anti-amnesic in the water maze test [1,6]; this dose works out to roughly 2mg in an adult human (70kgs). One study also used 1mg/kg in rats and found it to have anti-amnesic effects in rats; this dose would be ~17mg for a healthy adult human (70kgs) . Toxicity At the dose of 1mg/kg, the highest dose tested so far, it was found that Unifiram showed no toxicity and had no negative effects on motor coordination. This would suggest that a dose of .29mg/kg in an adult human should have no negative effects, and should be non-toxic . References 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. Naunyn Schmiedebergs Arch Pharmacol. 2003 Dec;368(6):538-45. Epub 2003 Nov 5.  Martini E, Norcini M, Ghelardini C, Manetti D, Dei S, Guandalini L, Melchiorre M, Pagella S, Scapecchi S, Teodori E, Romanelli MN. Design, synthesis and preliminary pharmacological evaluation of new analogues of DM232 (unifiram) and DM235 (sunifiram) as cognition modulators. Laboratory of Design, Synthesis and Study of Biologically Active Heterocycles (HeteroBioLab), Department of Pharmaceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy. Bioorg Med Chem. 2008 Dec 1;16(23):10034-42. doi: 10.1016/j.bmc.2008.10.017. Epub 2008 Oct 11.  Martini E, Ghelardini C, Bertucci C, Dei S, Gualtieri F, Guandalini L, Manetti D, Scapecchi S, Teodori E, Romanelli MN. Enantioselective synthesis and preliminary pharmacological evaluation of the enantiomers of unifiram (DM232), a potent cognition-enhancing agent. Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy. Med Chem. 2005 Sep;1(5):473-80.  Romanelli MN, Galeotti N, Ghelardini C, Manetti D, Martini E, Gualtieri F. Pharmacological characterization of DM232 (unifiram) and DM235 (sunifiram), new potent cognition enhancers. Dipartimento di Scienze Farmaceutiche, University of Florence, Sesto Fiorentino, Italy. CNS Drug Rev. 2006 Spring;12(1):39-52.  Scapecchi S, Martini E, Manetti D, Ghelardini C, Martelli C, Dei S, Galeotti N, Guandalini L, Novella Romanelli M, Teodori E. Structure-activity relationship studies on unifiram (DM232) and Sunifiram (DM235), two novel and potent cognition enhancing drugs. Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via G. Capponi 9, I-50121, Firenze, Italy. Bioorg Med Chem. 2004 Jan 2;12(1):71-85.  Ghelardini C, Galeotti N, Gualtieri F, Manetti D, Bucherelli C, Baldi E, Bartolini A. The novel nootropic compound DM232 (UNIFIRAM) ameliorates memory impairment in mice and rats. Drug Dev. Res., 56: 23–32. doi: 10.1002/ddr.10055.  - See more at: http://www.smarternootropics.com/unifiram/#sthash.Tw9dJitb.dpuf