30 replies to this topic

[Ben]

Recently there's been some discussion on the research nootrope: IDRA-21. As evidenced here and here.

In one paper it was found that "1/1–3 μmol/kg given orally" improved cognition tasks in rats and monkeys for 3-4 hours.

Another paper states that:

"it can be estimated that IDRA 21 is approximately 10-fold more potent than aniracetam in antagonizing alprazolam-induced learning deficit. "


And that:

"Very likely IDRA 21 exerts its behavioral effects by antagonizing AMPA receptor desensitization."

I went to http://www.tocris.co...php?ItemId=1364 to see how much this costs to synthesize. Considering that the active dose is in the micrograms/kg, at 90 GPB per 10 mg, the substance can be made by a reputable lab. with COA. very cheaply.

Edited by Ben, 17 September 2011 - 01:42 PM.

[Raptor87]

Ivé also read about this...Anyone?

[Dirk_Diggler]

Very interesting find...

[QuantumTubule]

Usually the mood of action is a crediabile guide stick to guessing at effects. Therefore analysis of the Benefits/Liabilities of 'antagonizing AMPA receptor desensitization', should be conducted by someone competent (e.g PHD).
Im not claiming competence, however I would guess the benefits would be rather similar to aniracetam increased performance in some metrics, the Liabilities definitly will include greater excitoxicicty and increased long term potentiation, and some metrics of cognition will also be reduced i would guess it would induce mild stereotype for instance. Wheather there is a window for safe use is not known by me, There maybe some mediating factors that block excitoxicity at low doses.

The Pharamkenetics of the molecule and its target are also very important, the brain relies on temporal(space/time) plasticity to achieve cognitive function, high affinity ligands are more inclined to reduce this temporal plasticity, therefore often neuroactive drugs are formulated as a fragment of the active ligands, which requires various metabolic conversions to reach the bind.

I dont believe this forum should allow discussion of taking drugs that have not made it to phase 2 clinical trial. There just is not enough knowledge or competence around.

Aniracetam is a similar drug to this research one, although it does require higher doses, does this matter.


AND BEN BRO< SAY THIS FOR YOUR OWN GOOD< NEVER MESS AROUND WITH RESEARCH CHEMS OR EVEN VITAMINS< YOU MESSED UP, CONFUSSED MILLGRAMS FOR GRAMS< THATS ENOUGH OF A MISTAKE TO KILL WITH MOST SUBSTANCES. RETARD>

Edited by QuantumTubule, 16 September 2011 - 03:15 AM.

[Ben]

AND BEN BRO< SAY THIS FOR YOUR OWN GOOD< NEVER MESS AROUND WITH RESEARCH CHEMS OR EVEN VITAMINS< YOU MESSED UP, CONFUSSED MILLGRAMS FOR GRAMS< THATS ENOUGH OF A MISTAKE TO KILL WITH MOST SUBSTANCES. RETARD>

I misquoted the site I used to get the price for analysis--not the dosage (which I directly copied from the article.) Thanks for the tip on the mood of action though. I found it quite crediable. At least you've come to the right section of the forum.

[JChief]

While we are discussing experimental noots..

If there's one ampakine I'd like to try (and I'd assume to be more powerful) it'd be CX717. It appeared to be effective for ADHD yet the corrupt as ever FDA poo poo'd it on a "technicality" that Cortex tried to rebut without directly offending anyone. I suspect foul play as the FDA's stance is to continue to pump people full of amphetamines instead apparently .

"While this decision by the FDA represents a significant setback for the company, Cortex has a broad-based technology platform that is currently producing several other significant future clinical candidates." More here

Edited by JChief, 16 September 2011 - 06:35 AM.

[Ampa-omega]

Ben, can you give more information of which sites you're obtaining the actual figures from?

IDRA-21 is very interesting , I don't think people need to get too alarmist about the danger though.

All drugs are experimental, just because scientist don't fully know the workings of the brain.
if you stay under the tested safe dosage it should be safe.

Edited by Ampa-omega, 16 September 2011 - 05:36 PM.

[Ben]

Ben, can you give more information of which sites you're obtaining the actual figures from?

See links in main post.

If anyone has some more info on this very interesting compound, please post.

7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine S,S-dioxide: a partial modulator of AMPA receptor desensitization devoid of neurotoxicity.

Impagnatiello F, Oberto A, Longone P, Costa E, Guidotti A.

Source

The Psychiatric Institute, Department of Psychiatry, University of Illinois College of Medicine, Chicago, IL 60612, USA
.
Abstract
In cerebellar granule neurons of neonatal rats micromolar concentrations of 7-chloro-3-methyl-3,4-dihydro-2H-1,2, 4-benzothiadiazine S,S-dioxide (IDRA-21) and cyclothiazide, two negative modulators of the spontaneous agonist-dependent rapid desensitization of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA)-gated ion channels, facilitate AMPA receptor function by increasing the content of free cytosolic Ca2+ as measured by single-cell fura-2 acetoxymethyl ester (Fura-2) Ca2+-dependent fluorescence and intracellular Na+ measured with the sodium-binding bezofuran isophthalate acetoxymethyl ester fluorescence indicator. IDRA-21 increases intracellular Na+ transient with a threshold (5 microM) that is approximately 10 times higher and has an intrinsic activity significantly lower than that of cyclothiazide. By virtue of its low intrinsic activity, IDRA-21 elicits a free cytosolic Ca2+ transient increase that is shorter lasting than that elicited by cyclothiazide even when the drug is left in contact with cultured granule cells for several minutes. Additionally, while dose dependently, 5-25 microM cyclothiazide in the presence of AMPA is highly neurotoxic, IDRA-21 (up to 100 microM) is devoid of neurotoxicity. The neurotoxicity elicited by cyclothiazide persists in the presence of dizocilpine (an antagonist of N-methyl-D-aspartate-selective glutamate receptors) but is blocked by 2,3-dihydroxy-6-nitrosulfamoylbenzo[f]quinoxaline (a competitive AMPA receptor antagonist) and the 1-(aminophenyl)-4-methyl-7, 8-methylendioxy-5H-2,3-benzodiazepine (GYKI 52466; a noncompetitive AMPA receptor antagonist). Since the doses of IDRA-21 that enhance cognitive processes in rats and monkeys are several orders of magnitude lower than those required to elicit marginal neurotoxicity in cultured neurons, it can be surmised that IDRA-21 is a potent cognition-enhancing drug virtually devoid of neurotoxic liability because it acts as a partial negative allosteric modulator of AMPA receptor desensitization.

→ source (external link)

Edited by Ben, 17 September 2011 - 01:57 PM.

[MrHappy]

..and yet it is a benzo. I think I'd rather become a hardcore drug addict and give up heroin. Benzos are not easy to get off at all.

[Dirk_Diggler]

..and yet it is a benzo. I think I'd rather become a hardcore drug addict and give up heroin. Benzos are not easy to get off at all.

I second that...benzo withdrawal, as with most GABAergic drugs, can kill you.

[Ampa-omega]

i see, the idea being that since you can dose so low you can make it more affordable, that would make it an overlooked but available option to most buyers then, My question is does it actually produce a statistically significant effect at such low concentrations that would make it worth buying? It seems to have a good safety profile.

heres another supplier with some data
http://www.axxora.co...D%3DALX-550-062

here is an blog i found in layman's terms on IDRA-21
http://chemicalwizardry.wordpress.com/

Heres some more research:

→ source (external link)

"IDRA-21, which does not have the peripheral side effects associated with diazoxide and cyclothiazide and unlike the latter rapidly increases synaptic potentials (Arai et al., 1996a), was the first benzothiadiazide examined in behavioral tests (Zivkovic et al., 1995). However, IDRA-21 has modest potency, with concentrations above 200 μM typically needed to enhance excitatory transmission in hippocampal slices (Arai et al., 1996a). Our efforts as well as those of others (Desos et al., 1996; Pirotte et al., 1998) have therefore been directed at finding analogs that have higher potency yet maintain effect profiles that are suitable for behavioral applications. In the present project, we systematically modified substituents at various locations around the benzothiadiazide core of IDRA-21 and measured the effects on various aspects of AMPA receptor operation. Some of the modifications resulted in compounds that have much greater potency than IDRA-21 and have effects on AMPA receptor kinetics that differ radically from those of cyclothiazide. A comprehensive description of the compounds that were synthesized and examined in this study is given elsewhere (Phillips et al., 2002), and some data have been presented in abstract form (Arai et al., 1999)."

→ source (external link)

→ source (external link)

"We examined IDRA21's effect upon AMPAergic synaptic currents and whole-cell glutamate currents in cultured rat hippocampal neurons to determine whether IDRA21 was a partial modulator of AMPA receptor desensitization and deactivation. Comparable to cyclothiazide, IDRA21 prolonged AMPAergic autaptic currents (5.6 times control, EC₅₀150 μM) and slowed the rate of AMPA deactivation (3 times control) following 1-ms applications of 1 mM glutamate to excised, outside-out membrane patches. IDRA21 also augmented autaptic GABA currents by 27 ± 8.1%, although it had two opposing effects, reducing the peak amplitude versus prolonging autaptic GABA currents. IDRA21 (200 μM) inhibited whole-cell GABA currents elicited by exogenously applied 1 mM GABA by 41 ± 11%. At sufficient concentrations, IDRA21 reduced AMPA receptor desensitization and slowed the rate of deactivation, most consistent with full agonist activity with lower potency compared to cyclothiazide. IDRA21 slightly augments GABAergic synaptic currents."

http://pubs.acs.org/....1021/bi901127s


http://www.ncbi.nlm....pubmed/12181433

http://www.ncbi.nlm....les/PMC2756660/

Figure 1


(A) Structure of the GluR2 S1S2 dimer in two orientations. One monomer is shown in shades of blue and the other in shades of green. ALTZ is bound in two copies to the dimer interface, and glutamate is bound to the agonist-binding site. The structures on the left illustrate the symmetrical dimer interface, and the structures on the right illustrate the inverted U-shaped cleft between the subunits. (B) Illustration of the five subsites in the binding surface by superimposition of structures determined previously. The ribbon representation of the protein is from the cyclothiazide structure (1lbc; 18). The carbon atoms in CTZ are colored white. Also shown are the positions for aniracetam (2al5; carbons colored yellow; 20), CX614 (2al4; carbons colored cyan; 20), and a dimeric biarylpropylsulfonamide (3bbr, carbons colored green, 21). In the cases of aniracetam and CX614, only one of two orientations is shown.

http://www.mendeley....-ampa-receptor/

http://www.ncbi.nlm....les/PMC2656388/

http://onlinelibrary...10.00726.x/full

sorry if it's a bit hard to navigate or read, i was trying to include as best the links i could.

Edited by Ampa-omega, 18 September 2011 - 12:31 AM.

[Ampa-omega]

..and yet it is a benzo. I think I'd rather become a hardcore drug addict and give up heroin. Benzos are not easy to get off at all.

ya seems to be part of its nootropic mechanism of action:

"IDRA21 also augmented autaptic GABA currents by 27 ± 8.1%, although it had two opposing effects, reducing the peak amplitude versus prolonging autaptic GABA currents. IDRA21 (200 μM) inhibited whole-cell GABA currents elicited by exogenously applied 1 mM GABA by 41 ± 11%. At sufficient concentrations, IDRA21 reduced AMPA receptor desensitization and slowed the rate of deactivation, most consistent with full agonist activity with lower potency compared to cyclothiazide. IDRA21 slightly augments GABAergic synaptic currents."

So what kind of benzodiazepine is it? (did you get mixed up with benzothiadiazine?) doesn't look to be pro GABA.

Edited by Ampa-omega, 18 September 2011 - 12:59 AM.

[Ampa-omega]

"We and others have searched for specific modifiers of the rapid desensitization of AMPA responses in hippocampal slices using the patch-clamp technique. Aniracetam (1-(4-methoxybenzoyl)-2-pyrrolidinone) and diazoxide (7-chloro-3-methyl-2H-1,2,4-benzo-thiadiazine 1,1-dioxide) (1 mM) increased glutamate-activated currents recorded from voltage-clamped CA1 pyramidal neurons in presence of 5 microM MK-801 (dizocilpine; 10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine) by 2.5 fold. Cyclothiazide (3-bicyclo[2.2.1]hept-5-en-2-yl-6-chloro-3,4-dihydro-2H-1,2,4-benzoth ia diazine-7-sulfonamide 1,1-dioxide) (100 microM), a chemical congener of diazoxide, completely removed the desensitization of the AMPA response measured with fast application in excised outside-out patches. At this concentration cyclothiazide produced an 18 fold enhancement of the glutamate current. Eighteen diazoxide analogues (2H-1,2,4-benzothiadizines: IDRA 2-19) were then tested but none of them was as effective as diazoxide. Three analogues of cyclothiazide (3,4-dihydro-2H-1,2,4-benzothiadiazines: IDRA 20-22) were also tested and none of them were as potent as the parent compound. However, IDRA 21 produced a response 3 times larger than diazoxide. Moreover, while cyclothiazide and diazoxide potentiated kainate responses for all the doses that decreased AMPA receptor desensitization, IDRA 21, similarly to aniracetam, inhibited AMPA receptor desensitization preferentially. These results suggest that similarly to NMDA receptors the structure of AMPA receptors may include a center that regulates desensitization."

Edited by Ampa-omega, 18 September 2011 - 01:26 AM.

[Ben]

MrHappy, if my understanding is correct, this drug should have the opposite effect of a benzo. considering this quote from AlphaOmega's post:
"[IDRA-21] inhibited whole-cell GABA currents elicited by exogenously applied 1 mM GABA"

[MrHappy]

Although that looks very much like it may be the case, before trying it myself, I'd love to read about the experiences of someone else who is willing to take it for 3-6 months and then try to give it up.

[Healthy Tony]

Although that looks very much like it may be the case, before trying it myself, I'd love to read about the experiences of someone else who is willing to take it for 3-6 months and then try to give it up.

If you pay for it I will gladly be your guinea pig

[QuantumTubule]

I have read quite a few reports of drug development and one strong point I noticed was this, That In Vitro studies of toxicity are notoriously weak compared to the required standard before Human consumption, because the tissue is seperated in a test tube numerous system are rendered idle, therefore the ligand may still be highly toxic In Vivo. Furthermore In Vitro tissue samples are degenerating rather quickly, over 24 hours you can have say 20% neuron loss in control, this makes determining a weak toxicity difficult, think statistical significance, would you like to lose 2% of your neurons per dose?
Furthermore neuropharamacuticals can be toxic through altering signal transduction in the CNS, there are quite a few failed drugs, that while not toxic caused excessive stimulation of particular nodes of the brain, eg increased Frontal stimulation, increases Cereblar stimulation leading punjukie neuron loss and which caused cerebalar atrophy which cause profound CNS atrophy.

If I was interested in taking this product, I would consider it necessary to perform lifetime assessment of physical and mental health in a mamaul, preferentially monkeys(but this would take to long),(try rats first, still up to 36months). I would start at a equivalent 'childhood' age and would expect to see improved cognition performance until a point similar to control animal average death age. (Yes Control would be required), To assess cognitive performance a enriched envirnoment would be required aswell as a throughly astute mind of the researcher, many metrics required.

PS Toxicity also often results on drug withdrawl, this can be profound.

It is an interesting compound, Anyone got In Vivo Tox studies, even short term

[Ampa-omega]

very nice reply,

we need some in vivo data in humans,
but human studies are probably avoided and replaced by studies with monkeys

I'm not sure how the oral doses used in monkeys differ in humans, that is something needed to figure out.

i found some info on toxicity from here

http://books.google....idra-21&f=false

it was said to have effect orally in monkeys at low concentrations and far from the dose required to cause toxicity in the in vitro experiments.-though i cant remember exactly where i read that.

Edited by Ampa-omega, 19 September 2011 - 05:38 PM.

[QuantumTubule]

That material should be referenced in the back of the book(Can you find this), I imagine there will be full pharamakenetic data(volume of distribution etc) for the animal model, Pharamakenetics for rats are not really a yard stick for the human profile, however monkeys can be for most substances.

[Ampa-omega]

I'm busy at the moment but ill be on it when i get the time,i'll try to see if i could find the book file online.there are manny references available which could be seen listed on pages 94-96
maybe we could find the conversion/distribution data we are looking for in the available references
or links from them.

Edited by Ampa-omega, 21 September 2011 - 06:31 PM.

[Googoltarian]

I'm busy at the moment but ill be on it when i get the time,i'll try to see if i could find the book file online.there are manny references available which could be seen listed on pages 94-96
maybe we could find the conversion/distribution data we are looking for in the available references
or links from them.

http://www.longecity...post__p__485182

[Ampa-omega]

I'm busy at the moment but ill be on it when i get the time,i'll try to see if i could find the book file online.there are manny references available which could be seen listed on pages 94-96
maybe we could find the conversion/distribution data we are looking for in the available references
or links from them.

http://www.longecity...post__p__485182

thanks for that, googolitarian, appreciate it.
but still need to make sure that its effective dose is not at the concentration that is toxic, higher doses of idra21 potentiate toxicity, its a pretty cool cognitive enhancer but it could cause toxicity at the wrong dose so need to make sure on that. dose thats effective + reletively harmless..

the text from the pic i posted:
one still unresolved issue is the large discrepancy between the concentrations of paarm's which are active in vitro and their plasma/brain concentrations in vivo. concentrations of idra21 to measurably effect ampa Receptor channel kinetics or synaptic transmission are in the range of 200 to 1000 µM, effective dose in animal experiments 10mg/kg induce peak brain levels in the range of 10 to 30 µM (which is saying that taking the 10mg/kg µM only induces 10-30µM in the brain. which isn't really effective, you need at least 200µM -1000µM ) ..from animal experiments. unless..im getting my self confused here. so would upping the dose to get 200µM in the brain be safe? I must be confusing myself.

Edited by Ampa-omega, 22 February 2012 - 10:35 PM.

[Ampa-omega]

theres no point in idra-21 if it's not cost effective, thats what really matters, if someone knows what they are doing and can get it at a low price then it could be a good nootropic, idra seems to have effect on kainate receptors, which is interesting. and oh god do i need to organize my older post. hopefully when i get a better grip on this stuff, should definitely try to make this less confusing.

Edited by Ampa-omega, 23 February 2012 - 10:50 PM.

[zeroskater6979]

what company invented this drug? and has it ever been tested in humans?

[Ampa-omega]

what company invented this drug? and has it ever been tested in humans?

most of these research chemicals have not been tested on humans because they first must move through different stages of research, testing compounds also requires opening up the brain which is why they first test on animals, once they get preclinical safety data they then move on to clinical applications and phase 1 testing. wikipedia will give you references on the compounds and you probably have to search around for older studies to know who invented the compounds, but some animal studies show it to be nontoxic up to a certain dose.
http://www.reference...1/mD001581.html
http://pubchem.ncbi....i?cid=3688#x281
http://en.wikipedia....i_Lilly.2Fother

Edited by Ampa-omega, 23 February 2012 - 11:24 PM.

[zeroskater6979]

if idra-21 were considered safe and effective i think it would have moved to humans by now. it may be non toxic and useful in preclinical studies but it seems that idra fell dead from the lab bench. it does however, seem like a hopeful drug to me, a layman, but to those working with it, it may be hopeless.

[Ampa-omega]

if idra-21 were considered safe and effective i think it would have moved to humans by now. it may be non toxic and useful in preclinical studies but it seems that idra fell dead from the lab bench. it does however, seem like a hopeful drug to me, a layman, but to those working with it, it may be hopeless.

too early to jump to conclusions on these things if you don't know, its probably just being used as a lead compound for developing analogues with better biovailability and receptor pharmacology. it is listed as an investigational new medicine after all.

Edited by Ampa-omega, 24 February 2012 - 12:51 AM.

[zeroskater6979]

you're definitely right ampa, i don't know for sure what idra's scientists are doing and what they plan to do. It just seems that something would have happened by now. I havent seen any published info on new analogues or prospects of moving forward with human studies. It's been around since at least '93 (thats the earliest thing i could find on google scholar) though probably earlier. Like i said though, i am hopeful. Something will happen sooner or later whether its idra or cx717 or the hundred other ampakines that are being studied. But you're right, they're probably trying to create an analogue with better pharmacological properties.

[Reformed-Redan]

One of the reasons why this compound was dropped was because it was very potent and there were concerns about glutamate excitotoxicity. There are some newer alternatives; but, if you're a diehard nootropic enthusiast you can take a neuroprotective compound (something that increases BDNF, as BDNF is the most potent neuroprotective compound to my knowledge) to lessen the chances of damage.

[MangekyōPeter]

Just wanted to inform people that it appears NSN has IRDA-21 in stock as of yesterday.