5 replies to this topic

[Reformed-Redan]

Doing some research and came across something really promising. The structure seems rather simple to synthesize and the doses are minute. See:

 

http://www.ncbi.nlm....pubmed/20965497

 

Immediate and sustained improvements in working memory after selective stimulation of α7 nicotinic acetylcholine receptors.

Castner SA1, Smagin GN, Piser TM, Wang Y, Smith JS, Christian EP, Mrzljak L, Williams GV.

Author information

 

Abstract

BACKGROUND:

Nicotine improves cognition in humans and animal models of neuropsychiatric disorders. Here, we sought to establish whether selective stimulation of the neuronal nicotinic α7 receptor could improve spatial working memory in nonhuman primates.

METHODS:

Beginning with an estimated dose range from rodent studies, the dose of the α7 agonist AZD0328 was titrated for a significant impact on working memory in rhesus macaques after acute administration. After training to stability on the spatial delayed response task, subjects were administered AZD0328 (1.6 ng/kg-.48 mg/kg; intramuscular) or vehicle 30 min before cognitive testing. AZD0328 (1 ng/kg-1.0 μg/kg; intramuscular) was then administered in a repeated, intermittent ascending dose regimen where each dose was given in two bouts for 4 days with a 1-week washout in between bouts, followed by 2-week washout.

RESULTS:

Acute AZD0328 improved cognitive performance when the dose was titrated down to .0016 and .00048 mg/kg from a cognitively impairing dose of .48 mg/kg. In a subgroup, sustained enhancement of working memory was evident for 1 month or more after acute treatment. Immediate and sustained cognitive enhancement was also found during and after repeated administration of AZD0328 at .001 mg/kg.

CONCLUSIONS:

These findings demonstrate that extremely low doses of a nicotinic α7 agonist can have profound acute and long-lasting beneficial consequences for cognition, dependent upon the integrity of dorsolateral prefrontal cortex. Thus, the α7 receptor might have a fundamental role in the neural circuitry of working memory and in the synaptic plasticity upon which it might depend.

http://www.sciencedi...006295209006364

 

 

AZD0328, a novel spirofuropyridine neuronal nicotinic receptor partial agonist, was used to investigate the role of α7 neuronal nicotinic receptor (NNR) activation in the modulation of midbrain dopamine neuron function, cortical dopamine release and on two behavioral tasks known to be dependent on optimal levels of cortical dopamine. In vivo recordings from area 10 (ventral tegmental area) in rat brain showed an increased firing of putative dopamine neurons in response to low (0.00138 mg/kg) doses of AZD0328. Bursting patterns of dopamine neuron activity remained largely unchanged by application of AZD0328. In vivo microdialysis in awake rats showed an increase in extracellular prefrontal cortical dopamine in response to low doses of AZD0328. Compound-stimulated dopamine release showed an inverted dose effect relation that was maximal at the lowest dose tested (0.00178 mg/kg). Peak extracellular dopamine levels were reached 2 h after dosing with AZD0328. Acquisition of operant responding with delayed reinforcement in rats was dose dependently enhanced by AZD0328 with a plateau effect measured at 0.003 mg/kg. This effect was blocked by pre-treatment of animals with the selective α7 antagonist methyllycaconitine. AZD0328 improved novel object recognition in mice over a broad range of doses (0.00178–1.78 mg/kg) and the compound effect was found to be absent in homozygous α7 KO animals. Together, these data indicate that selective interaction with α7 NNRs by AZD0328 selectively enhances midbrain dopaminergic neuronal activity causing an enhancement of cortical dopamine levels; these neurochemical changes likely, underlie the positive behavioral responses observed in two different animal models. Our results suggest selective α7 NNR agonists may have significant therapeutic utility in neurologic and psychiatric indications where cognitive deficits and dopamine neuron dysfunction co-exist.

 

 

 

All info on AZD0328, here

http://www.google.co...8115139A1?cl=en

Edited by yadayada, 26 April 2014 - 05:53 PM.

[Jeoshua]

Well, its patented, first off. Doesn't that mean it's pretty much hands off for anything except wildly variant derivatives or cousins of this?

Second, that potency is very extreme. At 0.0001932 mg/kg HED, meaning 13.524 μg per dose, that's extremely powerful, more powerful than even LSD (although similar to the low doses of LSD that people have reported as having beneficial nootropic effects). There isn't any hint of what kind of route of administration that is. It's likely not oral, at that dose, so that points to IV or IM or something similar.

Additionally, there isn't a lot on that molecule. This would be an excellent lead chemical, if they can figure out which portion of this is the specificity moiety. They need to hire a Shulgin to work on this.

Edited by Jeoshua, 26 April 2014 - 06:19 PM.

[Dazzcat]

If this compound lacks 5ht3 antagonism then we might find it could potentially cause nausea,  I think 5ht3 binding activity is an important property when it comes to a7 nicotinic agonist as suggest by the research into evp-6124.

 

 

 

[Reformed-Redan]

Well, its patented, first off. Doesn't that mean it's pretty much hands off for anything except wildly variant derivatives or cousins of this?

Second, that potency is very extreme. At 0.0001932 mg/kg HED, meaning 13.524 μg per dose, that's extremely powerful, more powerful than even LSD (although similar to the low doses of LSD that people have reported as having beneficial nootropic effects). There isn't any hint of what kind of route of administration that is. It's likely not oral, at that dose, so that points to IV or IM or something similar.

Additionally, there isn't a lot on that molecule. This would be an excellent lead chemical, if they can figure out which portion of this is the specificity moiety. They need to hire a Shulgin to work on this.

So, was NSI-189 and we still have group buys going on, lol. As for dosage, a prepared amount can be made in a solution and then distributed. I don't see the problem here. It's like, why would you NOT want to have any group buy. Like what needs convincing anyone, NZT-like properties? 

[Jeoshua]

Okay, that answers that question about legality. Just so long as we don't sell it for whatever purpose they intended it for it should be perfectly legal, right?

And the only reason that I won't be participating in any potential group buy is being broke. I do think this is a very power potential therapy, and it is exceedingly promising as an a7NR(a). I just think that, in the long run, this chemical will be used as a lead chemical similar to the 2C series. There are no substitutions on any of the rings, and if reading PIHKAL and TIHKAL have taught me anything, it's that drugs that are extremely similar in structure can be changed drastically by changing the substitutions on their various rings; sometimes they become different in effect, sometimes they gain another feature, sometimes they become less potent, and this compound has potency TO SPARE!

The only real downside I can think of to this chemical is that changes in cognition were observed for a month after acute dosage. There is no telling how this qualitatively affects a human being, yet. If it helps your memory but (maybe) makes you feel icky for a whole month after 13 mcg (and that's a fairly high dose according to this information), the effects of a "cognitively impairing" overdose would be devastating.

Edited by Jeoshua, 27 April 2014 - 01:35 AM.

[yxmees]

So it's been 3 years, what has happened with this compound?