Sunifiram

Sunifiram (DM-235) is 1-(4-benzoylpiperazin-1-yl)propan-1-one, a synthetic piperazine compound studied as a cognition enhancer in rodents. A University of Florence group (Manetti, Ghelardini and colleagues) reported it in 2000 by simplifying the bicyclic series that produced unifiram (Manetti et al., 2000).

The developers describe it as structurally related to piracetam (Ghelardini et al., 2002) and to ampakines, a class of AMPA receptor modulators (Galeotti et al., 2003). PubMed indexes no study of it in people.

Those figures, the aliases and the structure come from PubChem CID 4223812.

Published work on Sunifiram falls into six areas. Each summary below states the model used. Most of it comes from the Florence group that made the compound, and all of it is animal, tissue or cell data.

Design and first reports

The group first described 1,4-diazabicyclo[4.3.0]nonan-9-ones with a piracetam-like profile in the mouse passive avoidance test; the most potent, DM232 (unifiram), was active at 0.001 mg/kg subcutaneously (Manetti et al., 2000). Simplifying that bicyclic core gave 1-acylpiperazines that kept high activity. The most potent, DM235 (later named Sunifiram), was also active at 0.001 mg/kg, both leads raised acetylcholine release in rat brain, and the molecular mechanism was left open (Manetti et al., 2000). Models: mice and rat brain.

Memory models in mice and rats

In the mouse passive avoidance test, Sunifiram prevented scopolamine-induced amnesia at 0.001 to 0.1 mg/kg intraperitoneally or 0.01 to 0.1 mg/kg by mouth, comparable to piracetam at 30 to 100 mg/kg, and prevented amnesia induced by mecamylamine, baclofen and clonidine without impairing rota-rod coordination. In rats, 0.1 mg/kg before each Morris water maze session prevented the scopolamine deficit (Ghelardini et al., 2002).

In olfactory bulbectomized (OBX) mice, which show hippocampus-dependent memory impairment, daily oral Sunifiram (tested at 0.01 to 1.0 mg/kg for 7 to 12 days) reversed Y-maze and novel object recognition deficits and restored hippocampal long-term potentiation (LTP), but did not change depression-like behavior (Moriguchi et al., 2013). Models: mice and rats.

AMPA receptor evidence

At 0.1 mg/kg intraperitoneally, Sunifiram and unifiram both reversed amnesia induced by the AMPA receptor antagonist NBQX in mice. In rat hippocampal slices, both reversed kynurenic acid's antagonism of NMDA-mediated noradrenaline release, an effect NBQX abolished (Galeotti et al., 2003). The group's 2006 review adds that neither compound showed affinity in binding studies for the main central receptors or channels (Romanelli et al., 2006). The AMPA link therefore rests on antagonist and brain-slice experiments, not on receptor binding data. Models: mice and rat hippocampal slices.

The NMDA receptor glycine site in hippocampal slices

In mouse hippocampal slices, a Tohoku University group found that 10 to 100 nM Sunifiram enhanced CA1 LTP, with a bell-shaped concentration curve peaking at 10 nM. The glycine-site antagonist 7-chlorokynurenic acid blocked this, the polyamine-site inhibitor ifenprodil did not, and slices first exposed to 300 µM glycine showed no enhancement.

Src, protein kinase Cα and CaMKII activity rose, with more AMPA and NMDA receptor phosphorylation, and the authors proposed that Sunifiram stimulates the NMDA receptor's glycine-binding site (Moriguchi et al., 2013). In OBX mice, the glycine-site inhibitor gavestinel inhibited its stimulation of CaMKII and PKC (Moriguchi et al., 2013). Models: mouse hippocampal slices and mice.

Unifiram and the analog program

Unifiram (DM232) is the bicyclic parent, a 2-pyrrolidinone ring fused to a piperazine with one stereocenter (PubChem CID 9861054). Its (R)-enantiomer matched the (S)-form's effects at 3- to 10-fold lower amounts in memory tests and in acetylcholine release from rat cortex (Martini et al., 2005). Structure-activity work produced no analog as potent as either parent, and two analogs instead induced amnesia nearly as potently as scopolamine (Scapecchi et al., 2004).

Some later analogs of Sunifiram and sapunifiram (MN19) matched the parents' potency in mice (Martini et al., 2009). In 2017 the group added hydrophilic groups to the piperazine ring so that a biotin tag could later be anchored to capture the compound's biological target (Martino et al., 2017). Models: rodents and rat brain tissue.

Status of the literature

PubMed indexes no clinical trial, case report or other study of Sunifiram in people, and ClinicalTrials.gov lists no trial (both searched October 2026). A 2025 review notes that neither Sunifiram nor unifiram was developed further in clinical trials (Vialko et al., 2025). Gualtieri, a co-author of the original papers, later wrote that neither compound was patented and that he found dozens of websites selling them, although only a few preclinical studies existed and their long-term toxicity was unknown (Gualtieri, 2016).

A 2022 paper on a new Sunifiram synthesis and carbamate hybrids, screened in A549 cells, was retracted in 2026 over incorrect or unverifiable references; the authors disagree with the retraction. It is not evidence (Agha et al., 2022). Models: reviews and cell culture.