Sunifuram: a simple & potent Piracetam analog

[Chimimanie]

Thanks to

Post 460406

(xeno_tropic: "Modafinil", Novel Discourse) who cited it, and to

Post 460426

(thallium: "There are similar compounds called Unifiram...", Novel Discourse) who gave me the structure, I became interested in sunifuram, DM235. That newly found analog of piracetam is ~1000 times more potent than the latter, beeing active between 0.5-5 mg (depends on mice dose extrapolation).

It is a nootropic, capable of reverse the amnesia induced by scopolamine, diphenhydramine, baclofen or a disease, such as Alzeihmer's and Parkinson's. (hopefully induced by salvia and ketamine too   ). Maybe it can be effective if there is no lesion too, as it was active on mice without one.  

Quote from

http://www.bentham.org/sample-issues/cpd8-2/gualtieri/gualtiei-ms.htm

:

Unifiram and sunifiram were able to revert amnesia induced by a variety of amnesing drugs such as diphenhydramine (antihistaminic), baclofen (GABAB agonist) and clonidine (a2 agonist) with a potency pattern similar to that reported for scopolamine. Moreover, they were active as well in a test (social learning) where there is no deficit in the cognitive functions.

This class of compound has very low toxicity, for instance in the mice the compound can be injected in 1000 times the active dose, without any colateral symptom, such as loss of motor coordination or difference in motility.

Even better, this pharmaceutical is one of the simplest of the Piracetam's SAR. Basically it is a piperazine substituted at one of its N with a benzoyl and at the other with a propionyl, making a diamide. It should be straightforward to made from N-benzyl-piperazine, and is a good way to get rid of that nasty BZP in a nice and useful fashion.

See structure here, compound sunifuram:

http://www.bentham.org/sample-issues/cpd8-2/gualtieri/fig4.gif

Here is an article on it:

Molecular Simplification of 1,4-Diazabicyclo[4.3.0]nonan-9-ones Gives Piperazine Derivatives That Maintain High Nootropic Activity.
Dina Manetti, Carla Ghelardini, Alessandro Bartolini, Silvia Dei, Nicoletta Galeotti, Fulvio Gualtieri, Maria Novella Romanelli, and Elisabetta Teodori, J. Med. Chem. 2000, 43, 4499-4507

https://www.thevespiary.org/rhodium/Rhodium/pdf/piperazine.nootropics.pdf

Abstract:

Several 4-substituted 1-acylpiperazines, obtained by molecular simplification of 4-substituted 1,4-diazabicyclo[4.3.0]nonan-9-ones, have been synthesized and tested in vivo on the mouse passive avoidance test, to evaluate their nootropic activity. The results show that, apparently, an N-acylpiperazine group can mimic the 2-pyrrolidinone ring of 1,4-diazabicyclo[4.3.0]nonan-9-one, as the compounds of the new series maintain high nootropic activity. Moreover molecular simplification produces more clear-cut structure-activity relationships with respect to the parent series. The mechanism of action also appears to be similar in the two series. In fact, although the molecular mechanism remains to be elucidated, the most potent compound of each class (DM232 and 13, DM235) is able to increase acetylcholine release in rat brain. Piperazine derivatives represent a new class of nootropic drugs with an in vivo pharmacological profile very similar to that of piracetam, showing much higher potency with respect to the reference compound. Among the compounds studied, 13 (DM235) shows outstanding potency, being active at a dose of 0.001 mg kg-1 sc.


Check also:

Patent EP1118612

Patent IT1304881

[xeno_tropic]

Piracetam is a kind of rigid GABA analog, as are all 'racetams. Which interests me, as I believe the center of intellect is in the cerebellum, or at least that it is key. The cerebellum has the most numerous and advanced set of GABA receptors in the brain. The cerebellar midline, the vermis, inhibits a part of the brain called the amygdala. The amygdala is mainly for emergencies, causing one to act first and analyze later. It is also involved in fear and aggression. The amygdala's inhibitory system is GABA-based.
 Thus I also believe intellect and emotion are intimately linked.
It is also interesting that piperazine is involved in these nootropic molecules, as piperazine is so similar to glycine anhydride in structure. There are many studies and patents involving large doses of glycine as a treatment for schizophrenia.
 It has been demonstrated by brain scans that a feature of Alzheimers' is not lowered activity, but overactivity.
I'm glad that larger doses aren't toxic, those sub-milligram levels worried me.
Also glad that the article contains a synth involving acetyl piperazine. That could be useful for other things.

[Rhodium]

I believe the center of intellect is in the cerebellum

You must feel pretty alone with that belief, right?

[Rhodium]

2-Pyrrolidinone moiety is not critical for the cognition-enhancing activity of piracetam-like drugs
Serena Scapecchi, Cecilia Martellia, Carla Ghelardini, Luca Guandalini, Elisabetta Martini and Fulvio Gualtieria
Il Farmaco, 58(9), 715-722 (2003)
DOI:

10.1016/S0014-827X(03)00111-3

Abstract
Following the indications of previous work, 2-pyrrolidinone moiety of piracetam and piracetam-like compounds has been opened to the corresponding amide derivatives. As found previously in the case of 1,4-diazabicyclo[4.3.0]nonan-9-one compounds, the cognition-enhancing activity of 2-pyrrolidinone compounds is maintained in most cases, suggesting that this moiety is not crucial for activity.

[Chimimanie]

DM235 (sunifiram): a novel nootropic with potential as a cognitive enhancer.
Ghelardini, C.; Galeotti, N.; Gualtieri, F.; Romanelli, M. N.; Bucherelli, C.; Baldi, E.; Bartolini, A. Naunyn-Schmiedeberg's Archives of Pharmacology  (2002),  365(6),  419-426.

http://members.lycos.co.uk/chimimanie/potentpiracetam2.pdf

Abstract

DM235 (sunifiram), a new compd. structurally related to piracetam, prevented the amnesia induced by scopolamine (1.5 mg kg-1 i.p.), after i.p. (0.001-0.1 mg kg-1) or oral (0.01-0.1 mg kg-1) administration, as shown by a passive avoidance test in mice.  The antiamnesic effect of DM235 was comparable to that of well-known nootropic drugs such as piracetam (30-100 mg kg-1 i.p.), aniracetam (100 mg kg-1 p.o.) or rolipram (30 mg kg-1 p.o.).  DM235 also prevented mecamylamine (20 mg kg-1 i.p.)-, baclofen (2 mg kg-1 i.p.)- and clonidine (0.125 mg kg-1 i.p.)-induced amnesia in the same test.  In the Morris water maze test with rats, scopolamine (0.8 mg kg-1 i.p.) inhibited the redn. of escape latency in both acquisition and retention/retraining tests.  DM235 (0.1 mg kg-1 i.p.), 20 min before each daily acquisition training, prevented the scopolamine-induced memory impairment.  DM235 (1 mg kg-1 i.p.) also reduced the duration of pentobarbitone-induced hypnosis in mice without modifying the induction time of hypnosis.  At the highest EDs, the investigated compd. neither impaired motor coordination (rota-rod test), nor modified spontaneous motility and inspection activity (Animex and hole board tests).  These results indicate that DM235, a compd. structurally related to piracetam, is a novel nootropic endowed with the capability to prevent cognitive deficits at very low doses.  Indeed, its potency is about 1,000 times higher than that of the most active piracetam-like compds. 


4-Aminopiperidine derivatives as a new class of potent cognition enhancing drugs.
Manetti, Dina; Martini, Elisabetta; Ghelardini, Carla; Dei, Silvia; Galeotti, Nicoletta; Guandalini, Luca; Romanelli, Maria Novella; Scapecchi, Serena; Teodori, Elisabetta; Bartolini, Alessandro; Gualtieri, Fulvio. Bioorganic & Medicinal Chemistry Letters  (2003),  13(14),  2303-2306.

http://members.lycos.co.uk/chimimanie/potentpiracetam3.pdf

Abstract

Extrusion of one of the nitrogens of the piperazine ring of potent nootropic drugs previously described gave 4-aminopiperidine analogs that maintained high cognition enhancing activity in the mouse passive avoidance test.  One of the new compds. may represent a new lead for the development of cognition enhancers useful to treat the cognitive deficit produced by neurodegenerative pathologies like Alzheimer's disease. 


Also there is this one I dont have access to:

The novel nootropic compound DM232 (unifiram) ameliorates memory impairment in mice and rats.
Ghelardini, Carla; Galeotti, Nicoletta; Gualtieri, Fulvio; Manetti, Dina; Bucherelli, Corrado; Baldi, Elisabetta; Bartolini, Alessandro. Drug Development Research  (2002),  56(1),  23-32.

Can someone post it?

[thallium]

Structure–activity relationship studies on unifiram (DM232) and sunifiram (DM235), two novel and potent cognition enhancing drugs
Scapecchi, S. et. al.
Bioorganic & Medicinal Chemistry 12 (2004) 71–85

Abstract:

Structure–activity relationships on two novel potent cognition enhancing drugs, unifiram (DM232, 1) and sunifiram (DM235, 2), are reported. Although none of the compounds synthesised reached the potency of the parent drugs, some fairly active compounds have been identified that may represent new leads to develop other cognition enhancing drugs. An interesting result of this research is the identification of two compounds (13 and 14) that are endowed with amnesingactivity (the opposite of the activity of the original molecules) and are nearly equipotent to scopolamine. Moreover, two compounds of the series (5 and 6) were found endowed with analgesic activity on a rat model of neuropathic pain at the dose of 1 mg/kg.

[7is]

Piracetam and other structurally related nootropics.
Gouliaev AH, Senning A.
Brain Res Brain Res Rev. 1994 May;19(2):180-222.

Nearly three decades have now passed since the discovery of the piracetam-like nootropics, compounds which exhibit cognition-enhancing properties, but for which no commonly accepted mechanism of action has been established. This review covers clinical, pharmacokinetic, biochemical and behavioural results presented in the literature from 1965 through 1992 (407 references) of piracetam, oxiracetam, pramiracetam, etiracetam, nefiracetam, aniracetam and rolziracetam and their structural analogues. The piracetam-like nootropics are capable of achieving reversal of amnesia induced by, e.g., scopolamine, electroconvulsive shock and hypoxia. Protection against barbiturate intoxication is observed and some benefit in clinical studies with patients suffering from mild to moderate degrees of dementia has been demonstrated. No affinity for the alpha 1-, alpha 2-, beta-, muscarinic, 5-hydroxytryptamine-, dopamine, adenosine-A1-, mu-opiate, gamma-aminobutyric acid (GABA) (except for nefiracetam (GABAA)), benzodiazepine and glutamate receptors has been found. The racetams possess a very low toxicity and lack serious side effects. Increased turnover of different neurotransmitters has been observed as well as other biochemical findings, e.g., inhibition of enzymes such as prolylendopeptidase. So far, no generally accepted mechanism of action has, however, emerged. We believe that the effect of the racetams is due to a potentiation of already present neurotransmission and that much evidence points in the direction of a modulated ion flux by, e.g., potentiated calcium influx through non-L-type voltage-dependent calcium channels, potentiated sodium influx through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor gated channels or voltage-dependent channels or decreases in potassium efflux. Effects on carrier mediated ion transport are also possible.