9 replies to this topic

[knockout_mice]

Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel a4b2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N=243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4mg once daily (QD)) or 4mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners' Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4mg BID ABT-894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of a4b2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted.

http://www.ncbi.nlm....les/PMC3547191/

Attentional impairments are found in a range of neurodegenerative and neuropsychiatric disorders. However, the development of procognitive enhancers to alleviate these impairments has been hindered by a lack of comprehensive hypotheses regarding the circuitry mediating the targeted attentional functions. Here we discuss the role of the cortical cholinergic system in mediating cue detection and attentional control and propose two target mechanisms for cognition enhancers: stimulation of prefrontal a4b2* nicotinic acetylcholine receptors (nAChR) for the enhancement of cue detection and augmentation of tonic acetylcholine levels for the enhancement of attentional control.

While the literature on specific a4b2* agonists in humans is sparse, these agonists appear to have more robust attentional enhancement effects than those seen with nicotine in patient populations such as age associated memory impairment (Dunbar et al., 2007) and schizophrenia (Taylor et al. 2011). Interestingly, clinical trials on the a4b2* agonist ABT-089 demonstrate this agonist can robustly improve attention in adult ADHD patients (Wilens et al., 2006; Apostol et al., 2012), but not in pediatric ADHD patients (Wilens et al., 2011).

http://www.ncbi.nlm....les/PMC3445745/

What do you think?

Edited by mice, 04 April 2014 - 05:12 PM.

[xks201]

Quite fascinating

[therein]

This is very interesting. Would anyone be down for a group buy?

[xks201]

Yeah I'm kind of enamored with this compound. I could lead it after I get dihexa sent out. That probably won't be for 4 to 5 more weeks though.

[mait]

Nefiracetam seems to have similar effect on a4b2 nACh receptors.

 

From Biological Pharmacology Bulletin.  27 (11) pp. 1701—1706 (2004):

 

 

No strategies for curing Alzheimer’s disease have been developed yet as we do not know the exact cause of the disease. The only therapy that is available for patients is symptomatic treatment. Since Alzheimer’s disease is associated with downregulation of the cholinergic system in the brain, its stimulation is expected to improve the patients’ cognition, learning, and memory. Four anticholinesterases have been approved in the U.S.A. for the treatment of Alzheimer’s disease patients. However, because of the inhibition of cholinesterases, these drugs have side effects and their effectiveness does not last long. Thus new approaches are needed. One approach is to stimulate directly nicotinic acetylcholine (nACh) receptors in the brain, and another is to stimulate NMDA receptors which are also known to be downregulated in Alzheimer’s patients. Nefiracetam has been shown to potentiate ACh currents in the a4b2 receptor of rat cortical neurons with a bell-shaped dose–response relationship and the maximum effect at 1 nM. This effect was exerted via Gs proteins. The a7 receptor was almost unaffected by nefiracetam. Nefiracetam also potentiated NMDA currents with the maximum effect at 10 nM via interaction with the glycine-binding site of the receptor. Galantamine had a moderate potentiating effect on the a4b2 receptor and potentiated NMDA currents with the maximum effect at 1 mM. However, galantamine did not interact with the glycine-binding site. Donepezil, a potent anticholinesterase, also potentiated NMDA currents at 1—10000 nM. In conclusion, these three drugs potentiate the activity not only of the cholinergic system but also of the NMDA system, thereby stimulating the downregulated nACh receptors and NMDA receptors to improve patients’ learning, cognition, and memory.

 

I have been using pregnenolone for NMDA agonism and nefiracetam for a4b2 agonism. Sadly continued dosing of pregnenolone has not been sustainable in long run - so I have just carried on with nefiracetam.

 

Edited by mait, 15 April 2014 - 01:14 PM.

[xks201]

Nefiracetam seems to have similar effect on a4b2 nACh receptors.

 

From Biological Pharmacology Bulletin.  27 (11) pp. 1701—1706 (2004):

 

 

No strategies for curing Alzheimer’s disease have been developed yet as we do not know the exact cause of the disease. The only therapy that is available for patients is symptomatic treatment. Since Alzheimer’s disease is associated with downregulation of the cholinergic system in the brain, its stimulation is expected to improve the patients’ cognition, learning, and memory. Four anticholinesterases have been approved in the U.S.A. for the treatment of Alzheimer’s disease patients. However, because of the inhibition of cholinesterases, these drugs have side effects and their effectiveness does not last long. Thus new approaches are needed. One approach is to stimulate directly nicotinic acetylcholine (nACh) receptors in the brain, and another is to stimulate NMDA receptors which are also known to be downregulated in Alzheimer’s patients. Nefiracetam has been shown to potentiate ACh currents in the a4b2 receptor of rat cortical neurons with a bell-shaped dose–response relationship and the maximum effect at 1 nM. This effect was exerted via Gs proteins. The a7 receptor was almost unaffected by nefiracetam. Nefiracetam also potentiated NMDA currents with the maximum effect at 10 nM via interaction with the glycine-binding site of the receptor. Galantamine had a moderate potentiating effect on the a4b2 receptor and potentiated NMDA currents with the maximum effect at 1 mM. However, galantamine did not interact with the glycine-binding site. Donepezil, a potent anticholinesterase, also potentiated NMDA currents at 1—10000 nM. In conclusion, these three drugs potentiate the activity not only of the cholinergic system but also of the NMDA system, thereby stimulating the downregulated nACh receptors and NMDA receptors to improve patients’ learning, cognition, and memory.

 

I have been using pregnenolone for NMDA agonism and nefiracetam for a4b2 agonism. Sadly continued dosing of pregnenolone has not been sustainable in long run - so I have just carried on with nefiracetam.

 

And what does nefiracetam do for you?

[mait]

 

Nefiracetam seems to have similar effect on a4b2 nACh receptors.

 

From Biological Pharmacology Bulletin.  27 (11) pp. 1701—1706 (2004):

 

 

No strategies for curing Alzheimer’s disease have been developed yet as we do not know the exact cause of the disease. The only therapy that is available for patients is symptomatic treatment. Since Alzheimer’s disease is associated with downregulation of the cholinergic system in the brain, its stimulation is expected to improve the patients’ cognition, learning, and memory. Four anticholinesterases have been approved in the U.S.A. for the treatment of Alzheimer’s disease patients. However, because of the inhibition of cholinesterases, these drugs have side effects and their effectiveness does not last long. Thus new approaches are needed. One approach is to stimulate directly nicotinic acetylcholine (nACh) receptors in the brain, and another is to stimulate NMDA receptors which are also known to be downregulated in Alzheimer’s patients. Nefiracetam has been shown to potentiate ACh currents in the a4b2 receptor of rat cortical neurons with a bell-shaped dose–response relationship and the maximum effect at 1 nM. This effect was exerted via Gs proteins. The a7 receptor was almost unaffected by nefiracetam. Nefiracetam also potentiated NMDA currents with the maximum effect at 10 nM via interaction with the glycine-binding site of the receptor. Galantamine had a moderate potentiating effect on the a4b2 receptor and potentiated NMDA currents with the maximum effect at 1 mM. However, galantamine did not interact with the glycine-binding site. Donepezil, a potent anticholinesterase, also potentiated NMDA currents at 1—10000 nM. In conclusion, these three drugs potentiate the activity not only of the cholinergic system but also of the NMDA system, thereby stimulating the downregulated nACh receptors and NMDA receptors to improve patients’ learning, cognition, and memory.

 

I have been using pregnenolone for NMDA agonism and nefiracetam for a4b2 agonism. Sadly continued dosing of pregnenolone has not been sustainable in long run - so I have just carried on with nefiracetam.

 

And what does nefiracetam do for you?

 

 

 

I took nefiracetam last year, while writing my MSc thesis and while also taking R programming courses in Coursera and while doing so I noticed great benefits in tasks that involves sustained attention (such as academic writing) and maybe even in working memory. This year I resumed taking nefiracetam because I really struggled in getting my study related manuscript writing going and I immediately noticed positive results.

[Major Legend]

does the urinary tract problems happen with everyone for nefiracetam?

 

This is a interesting chemical. I wonder is it possible to be synthesized, it looks like a complicated molecule.

[Ultravioletbllc]

Some are currently available I believe ..... Let me look around and let you know

[thedevinroy]

http://www.ncbi.nlm....pubmed/24965900
 
Goes by a different name now: 

Sofinicline: a novel nicotinic acetylcholine receptor agonist in the treatment of attention-deficit/hyperactivity disorder

INTRODUCTION:
Psychostimulants are first-line treatments for attention-deficit/hyperactivity disorder (ADHD), but their tolerability profiles and individual response variability fuel a continuing search for alternative medications. The observation that nicotinic agents improve cognition has led pharmaceutical companies to explore the potential utility of agonists of the nicotinic acetylcholine receptor (nAChR) system for ADHD treatments.
AREAS COVERED:
This article reviews Phase I and Phase II trials of sofinicline (ABT-894), an agonist of the nAChR α4β2 subtype, as a potential non-stimulant treatment for ADHD. This includes one Phase II trial that compared sofinicline with atomoxetine, a noradrenergic reuptake inhibitor currently approved as a non-stimulant ADHD treatment. This article also reviews the chemistry, pharmacodynamics and pharmacokinetics of sofinicline.
EXPERT OPINION:
Sofinicline appears to be well tolerated and showing efficacy similar to that of atomoxetine. Although the number of patients studied to date is small, further evaluation of sofinicline in Phase II, and possibly Phase III, trials appears to be warranted. Additional studies are needed to explore the efficacy and tolerability of sofinicline with respect to: i) optimal dosing; ii) its use in combination with other medications for ADHD; and iii) its use in children and adolescents, who more commonly experience adverse effects when taking psychostimulant medications.

 

Looking for correlations between AChE activity and ADHD medications, and there weren't many... but there is definitely an effect on the dopamine system by acetylcholine and acetylcholine system by dopamine... it's just not directly to do with AChE.  Interesting that nefiracetam increases working memory.  That's a good sign that it helps with executive function disorders.

Edited by devinthayer, 25 July 2016 - 09:29 PM.