659 replies to this topic

[Milkyway]

Anyone yet have any idea when this structure will become known?

[Reformed-Redan]

I'm currently on vacation (getting off all my meds, yeah, hellish), I swear there is nothing else I'd rather get than this compound. Luckily, I may have found the structure of the compound and will be trying to work it out, since it's pretty complex. 

 

Anyone interested, just post here. 

[Milkyway]

Can you elaborate?  How would you have gotten the structure?  What do you mean "work it out"?  Just curious as I am also very interested in this.

[Reformed-Redan]

Can you elaborate?  How would you have gotten the structure?  What do you mean "work it out"?  Just curious as I am also very interested in this.

I'll let you know, ASAP. I'm pretty adamant on getting this compound too. 

[MangekyōPeter]

I'm currently on vacation (getting off all my meds, yeah, hellish), I swear there is nothing else I'd rather get than this compound. Luckily, I may have found the structure of the compound and will be trying to work it out, since it's pretty complex. 

 

Anyone interested, just post here. 

Uh, maybe he really does need to get off those meds
I'd have to nominate yadayada for the biggest character award, and/or maybe worst rep/shill for his company THT, lol

[Reformed-Redan]

 

I'm currently on vacation (getting off all my meds, yeah, hellish), I swear there is nothing else I'd rather get than this compound. Luckily, I may have found the structure of the compound and will be trying to work it out, since it's pretty complex. 

 

Anyone interested, just post here. 

Uh, maybe he really does need to get off those meds
I'd have to nominate yadayada for the biggest character award, and/or maybe worst rep/shill for his company THT, lol

 

Lol! THT is not my company. So chill. 

 

As for the structure of NRX-1074 here you go, let me know what you think, or not:

http://brevets-paten...0603_claims.pdf

[Milkyway]

Can anyone make heads or tails of this supposed structure.  Is this the real McCoy or is Yadayada's claim just yadayada.  Not trying to be insulting just want to know if this is for real.

[uralsky]

It was discussed earlier
http://www.longecity...sive-symptomes/
which one of the compounds claimed in WO201003757 could have been NRX-1074

Based on the logic of patent applications the ultimate compound wanted to be protected must be the one presented in claim 26, that is compound B http://patentimages....000020_0002.png
typ3z3r0 did not agree i was NRX-1074 though.

Edited by uralsky, 15 August 2014 - 03:22 AM.

[Reformed-Redan]

It was discussed earlier
http://www.longecity...sive-symptomes/
which one of the compounds claimed in WO201003757 could have been NRX-1074

Based on the logic of patent applications the ultimate compound wanted to be protected must be the one presented in claim 26, that is compound B http://patentimages....000020_0002.png
typ3z3r0 did not agree i was NRX-1074 though.

I'm fairly certain the structure is disclosed in that patent application. Only problem is which one... Once that's established it'll be short work to get it synthesized.

 

The patent image you listed i that of "Compound B", which has similar effects to GLYX-13 while being 20-fold more potent; but, does it decrease LTD?

Edited by yadayada, 15 August 2014 - 04:42 AM.

[uralsky]

http://www.google.co...2542254A1?cl=en

[0116] Compound B showed a 20-fold enhancement in potency compared to GLYX-13. 50 nM of this compound markedly enhanced both single shock (1A) and burst evoked (IB) INMDA , as well as doubling the magnitude of LTP (IE). In contrast, 1 μΜ NRX- 10,050 significantly reduced both single shock (1C) and burst evoked ((ID) INMDA, reminiscent of 100 μΜ GLYX-13. (See Figure 2).

[0117] AK-51 exhibited less potency than compound B, but a wider concentration range in its stimulatory actions (Figure 3). Both 100 nM (2A) and 1 μΜ NRX- 10,051 enhanced single- shock evoked INMDA , while 1 uM NRX- 10,051 doubled the magnitude of LTP (2D), while not altering LTD (2E).

[0118] AK-52 produced only a mild enhancement of single-shock evoked INMDA at a low concentration (100 nM; 3A), which converted to significant reduction in INMDA at a 1 uM concentration (3B). 100 nM AK-52 produced an enhancement of LTP similar in magnitude to compound B and AK-51, but this converted to a slight, but significant, reduction in LTP at the 1 μΜ concentration, without altering LTD.

[0119] These three compound showed about a 20-fold enhancement in potency compared to GLYX-13. Compound B is the most potent enhancer of INMDA at low concentrations (50 nM). While AK-51 enhancement of INMDA was smaller in magnitude, this effect remained when the AK-51 was increased 10-fold (100 nM to 1 μΜ). The AK-52 was the weakest enhancer of INMDA , and this effect reversed more quickly to a frank reduction in INMDA.

[0120] These compounds enhanced the magnitude of LTP to similar extents, approximately to a doubling. GLYX-13 was the only compound that could simultaneously increase LTP and reduce LTD: AK-52 did not affect LTD, even at a concentration that reduced INMDA- GLYX-13 can selectively enhance INMDA mediated by NMD A receptors containing NR2A/B subunits, and these receptors are localized to extrasynaptic loci and are more strongly activated by neuronal bursts that induce LTP. While all of the tested compounds have potent effects on LTP and INMDA, the lesser effects on LTD suggest that they have increased selectivity for NR2A/B containing NMD A receptor glycine sites than the GLYX-13.

Compound AK-51 however http://patentimages....000020_0003.png was the only tested in vivo in rats and showed efficacy in enhancing learning and memory when given orally at 1 mg/kg (equivalent to ~10mg human dose) Question is: why they did not show results of in vivo testing of compound B?

[Reformed-Redan]

http://www.google.co...2542254A1?cl=en
 

[0116] Compound B showed a 20-fold enhancement in potency compared to GLYX-13. 50 nM of this compound markedly enhanced both single shock (1A) and burst evoked (IB) INMDA , as well as doubling the magnitude of LTP (IE). In contrast, 1 μΜ NRX- 10,050 significantly reduced both single shock (1C) and burst evoked ((ID) INMDA, reminiscent of 100 μΜ GLYX-13. (See Figure 2).

[0117] AK-51 exhibited less potency than compound B, but a wider concentration range in its stimulatory actions (Figure 3). Both 100 nM (2A) and 1 μΜ NRX- 10,051 enhanced single- shock evoked INMDA , while 1 uM NRX- 10,051 doubled the magnitude of LTP (2D), while not altering LTD (2E).

[0118] AK-52 produced only a mild enhancement of single-shock evoked INMDA at a low concentration (100 nM; 3A), which converted to significant reduction in INMDA at a 1 uM concentration (3B). 100 nM AK-52 produced an enhancement of LTP similar in magnitude to compound B and AK-51, but this converted to a slight, but significant, reduction in LTP at the 1 μΜ concentration, without altering LTD.

[0119] These three compound showed about a 20-fold enhancement in potency compared to GLYX-13. Compound B is the most potent enhancer of INMDA at low concentrations (50 nM). While AK-51 enhancement of INMDA was smaller in magnitude, this effect remained when the AK-51 was increased 10-fold (100 nM to 1 μΜ). The AK-52 was the weakest enhancer of INMDA , and this effect reversed more quickly to a frank reduction in INMDA.

[0120] These compounds enhanced the magnitude of LTP to similar extents, approximately to a doubling. GLYX-13 was the only compound that could simultaneously increase LTP and reduce LTD: AK-52 did not affect LTD, even at a concentration that reduced INMDA- GLYX-13 can selectively enhance INMDA mediated by NMD A receptors containing NR2A/B subunits, and these receptors are localized to extrasynaptic loci and are more strongly activated by neuronal bursts that induce LTP. While all of the tested compounds have potent effects on LTP and INMDA, the lesser effects on LTD suggest that they have increased selectivity for NR2A/B containing NMD A receptor glycine sites than the GLYX-13.

Compound AK-51 however http://patentimages....000020_0003.png was the only tested in vivo in rats and showed efficacy in enhancing learning and memory when given orally at 1 mg/kg (equivalent to ~10mg human dose) Question is: why they did not show results of in vivo testing of compound B?

 

Compound B pretty closely resembles the effects listed as NRX-1074. I tried doing a search for "AK-74", you can imagine the results I got. Lol, mostly guns and stuff. But, if AK-51 is viable and not to hard to synthesize, I don't see why it shouldn't be a viable candidate as a precursor to NRX-1074, or at least to get a feel for the effects NRX-1074 has to present. 

 

I'm going to see if NRX-1051 can be made before we have a definitive answer on the structure of NRX-1074. If it's a relatively simple synthesis I don't see why not. :-) NRX-1051 is better than nothing.

Edited by yadayada, 16 August 2014 - 05:35 AM.

[uralsky]

Currently Naurex is recruiting for clinical trial of NRX-1074 at 1mg and 5mg IV dose.
the dose is consistent with Compound B or AK-51. What concerning is that they use IV administration and not oral. It seems to be not very bioavailable PO.

[Milkyway]

I thought the advantage of NRX 1074 is that it had good oral bioavailability.

[formergenius]

I think the reason they're assessing it IV initially is for better comparability against GLYX-13.
Uralsky, aside from them trialling it IV, have you any other reason to believe it wouldn't be decently bioavailable PO?

[uralsky]

I think the reason they're assessing it IV initially is for better comparability against GLYX-13.
Uralsky, aside from them trialling it IV, have you any other reason to believe it wouldn't be decently bioavailable PO?

no, i don't.

[Milkyway]

Any News, anyone?

[Reformed-Redan]

Still doing some more research into the compound. Need to know if NRX-1051 is bioavailable and if any more info can be found on NRX-1074.

[medicineman]

NRX-1074 isn't in there either unfortunately.

Neu2000 (2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid) seems pretty interesting, seeing as it's a selective antagonist of NR2B like CERC-301,  EVT 101 and  EVT 103, however is also a radical scavenger/spin-trapping molecule. AAD-2004, also in GNT Pharma's pipeline, looks interesting and shows promise for depression relief.

Neu2000..... I like.

[Reformed-Redan]

 

NRX-1074 isn't in there either unfortunately.

Neu2000 (2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid) seems pretty interesting, seeing as it's a selective antagonist of NR2B like CERC-301,  EVT 101 and  EVT 103, however is also a radical scavenger/spin-trapping molecule. AAD-2004, also in GNT Pharma's pipeline, looks interesting and shows promise for depression relief.

Neu2000..... I like.

 

RO-25-6981 is actually the only compound that is worth going after IMO. The antidepressant properties are incomparable along with the IC50 values at antagonizing NR2B channels. See:

 

Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro.

Fischer G1, Mutel V, Trube G, Malherbe P, Kew JN, Mohacsi E, Heitz MP, Kemp JA.

Author information

 

Abstract

The interaction of Ro 25-6981 with N-methyl-D-aspartate (NMDA) receptors was characterized by a variety of different tests in vitro. Ro 25-6981 inhibited 3H-MK-801 binding to rat forebrain membranes in a biphasic manner with IC50 values of 0.003 microM and 149 microM for high- (about 60%) and low-affinity sites, respectively. NMDA receptor subtypes expressed in Xenopus oocytes were blocked with IC50 values of 0.009 microM and 52 microM for the subunit combinations NR1C & NR2B and NR1C & NR2A, respectively, which indicated a >5000-fold selectivity. Like ifenprodil, Ro 25-6981 blocked NMDA receptor subtypes in an activity-dependent manner. Ro 25-6981 protected cultured cortical neurons against glutamate toxicity (16 h exposure to 300 microM glutamate) and combined oxygen and glucose deprivation (60 min followed by 20 h recovery) with IC50 values of 0.4 microM and 0.04 microM, respectively. Ro 25-6981 was more potent than ifenprodil in all of these tests. It showed no protection against kainate toxicity (exposure to 500 microM for 20 h) and only weak activity in blocking Na+ and Ca++ channels, activated by exposure of cortical neurons to veratridine (10 microM) and potassium (50 mM), respectively. These findings demonstrate that Ro 25-6981 is a highly selective, activity-dependent blocker of NMDA receptors that contain the NR2B subunit.

[Reformed-Redan]

The only problem with NR2B antagonists is that they are anti-nootropic from some studies I've read. But, IMO the potent anti-depressant effects are well worth the cost of antagonism at NR2B subunit. 

[VERITAS INCORRUPTUS]

Research with NR2B selective antagonist indeed appear to create a 'dumbing down' effect as opposed to a nootropic effect as seen with some other benficial and enhancing glutamatergic pathways.  

These agents that create a 'nooatrophic' effect, if you will, is obviously counter to important intended goals.

Edited by VERITAS INCORRUPTUS, 22 August 2014 - 02:48 PM.

[Matthew Butler]

I am interested

 

[Milkyway]

So has anyone come any closer to deciphering the structure of NRX 1074?  Forgive my stupidity but I don't quite understand.  Was the structure disclosed or wasn't it?

[Reformed-Redan]

I'm pretty confident Compound B listed in the patent paper is what NRX-1074 is. Just a matter of time to either confirm or refute this. 

[Milkyway]

Good.  Thanks for letting me know.

[Milkyway]

Once the structure is known how long do you think it will take to do a Group Buy?  I mean how long does it usually take between the time the structure is disclosed through getting it synthesized to actually receiving the product?  I know I am asking a lot of questions and that there is no definitive time  period but I wondered if anyone had an idea as I am very anxious to try this.

[Reformed-Redan]

Once the structure is known how long do you think it will take to do a Group Buy?  I mean how long does it usually take between the time the structure is disclosed through getting it synthesized to actually receiving the product?  I know I am asking a lot of questions and that there is no definitive time  period but I wondered if anyone had an idea as I am very anxious to try this.

There's no fixed date for that. All I can say is that the best that can be done is being done in regards to NRX-1074.

[Milkyway]

What is being done to decipher the content and disclose the enigma?  Is there anything I can do?  I am tired and tired of having depression, this thing I wear around like a grey cloak that envelopes my body and prevents my sensory perception from working with complete accuracy.  I want some type of genuinely effective treatment that is organic in nature but until then maybe something like NRX 1074 will suffice.  What specifically are we waiting for?

[Reformed-Redan]

What is being done to decipher the content and disclose the enigma?  Is there anything I can do?  I am tired and tired of having depression, this thing I wear around like a grey cloak that envelopes my body and prevents my sensory perception from working with complete accuracy.  I want some type of genuinely effective treatment that is organic in nature but until then maybe something like NRX 1074 will suffice.  What specifically are we waiting for?

Well, I'm trying to strongly get NRX-1074 and Ro-25-6981, both should completely obliterate depression, especially the latter. What are we waiting for? Well it takes time to synthesize these things. Just have to wait a little. I heard Lexapro works wonders. And it does work pretty well from personal experience. 

[Milkyway]

So, are you getting them synthesized and will they be available from a company.  As far as Lexapro goes, I tried it.  S.S.R.I.'s have been a curse on me.  They worked for a short while, yet now none of them work but I have to take at least some variety of them having gotten addicted.  I am anxious to try something different.