46 replies to this topic

[Reformed-Redan]

Lanicemine (AZD6765) is an NMDA antagonist developed by AstraZeneca,^[1] which is being studied for the treatment of major depression. It was originally developed as a neuroprotective agent, but was redeveloped as an antidepressant following the observation that the anesthetic drug ketamine has potent antidepressant effects, but also has hallucinogenic side effects which make it unsuitable for use as an antidepressant in most circumstances. Lanicemine is a low-trapping NMDA receptor antagonist which has been found in human trials to have similar rapid-acting antidepressant effects to ketamine, but with little or no psychotomimetic side effects.^[2]

^{It has a simple structure compared to GLYX-13. Anyone interested? Seems just as effective and without prominent side effects:}



KK nvm:

A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression.

Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA, Luckenbaugh DA.

Source

Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, MD 20892, USA. zaratec@mail.nih.gov
Abstract

BACKGROUND:

The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD).
METHODS:

In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on 2 test days 1 week apart. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on Days 1, 2, 3, and 7 postinfusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale.
RESULTS:

Within 80 min, Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d = .40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d = .49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects.
CONCLUSIONS:

In patients with treatment-resistant MDD, a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed.

[xks201]

Why not just take memantine? I'm ignorant.

[MasterHerb]

I am down

[protoject]

Why not just take memantine? I'm ignorant.

Memantine has other , perhaps unwanted mechanisms of action and has a half life of 50 hours

I'm also not aware that it is a robust antidepressant nor that it has been proven to be so.....

Btw, When i saw this in my science newsfeed, my hopes shot up , I must admit. It's always good to know that there may be a drug out there with equal efficiacy to an illegal recreational drug without the high, it kinda levels the playing field for us self-medicators a bit.

[Metagene]

GLYX-13 is sexier.

Will AZD6765 be cost effective?


I going to listen to this later

http://www.npr.org/2...ts-show-promise


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[Killword]

Very interested but does it need to be taken intravenously?

[typ3z3r0]

GLYX-13 and Lanicemine, as far as I know, aren't orally bioavailable unfortunately. However, NRX-1074, a follow-on to GLYX-13, is and is also several thousand times more potent than GLYX-13. Unfortunately, I can't find its structure anywhere.

[Reformed-Redan]

GLYX-13 and Lanicemine, as far as I know, aren't orally bioavailable unfortunately. However, NRX-1074, a follow-on to GLYX-13, is and is also several thousand times more potent than GLYX-13. Unfortunately, I can't find its structure anywhere.

THIS.

This is our #1 group buy after NSI-189. Everyone scour the interwebs for a structure. Look everywhere, through paywalls, everything!

[Metagene]

Just the patent if you hadn't already seen it:

https://www.google.c...ved=0CFgQ6AEwBQ


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[uralsky]

Just the patent if you hadn't already seen it:

https://www.google.c...ved=0CFgQ6AEwBQ

and more recent one
http://www.google.co...542254A1?cl=en' class='bbc_url' title='External link' rel='nofollow external'> http://www.google.com/patents/EP2542254A1?cl=en


[0071] Exemplary compounds include
http://patentimages....000020_0002.png
(compound B)

http://patentimages....000020_0003.png
(compounds AK-51 and AK-52)

Compound B is said to be 20x more potent than GLYX-13. Could be the one?

[Metagene]

That would seem logical. GLXY-13 is the lead compound and NRX-1074 is the second generation compound.

AK-51 Gen 3 and AK-52 Gen 4?

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Edited by Metagene, 19 November 2013 - 05:11 AM.

[typ3z3r0]

I looked at both patents earlier and Compound B, AK-51 and AK-52 likely aren't NRX-1074.

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.

NRX-10,051 likely isn't RX-1074 either. 1 μΜ of it "significantly reduced both single shock (1C) and burst evoked ((ID) INMDA, reminiscent of 100 μΜ GLYX-13", however it didn't alter LTD (long-term depression).

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).

Edited by typ3z3r0, 19 November 2013 - 08:37 AM.

[typ3z3r0]

Whoops. Accidentally removed the "N" from "NRX-1074".

[formergenius]

Anyone in San Francisco fancy visiting this gathering?
Perhaps they'll unveil its structure there?
edit: Thanks to alex921 for informing me of this.

Edited by formergenius, 11 January 2014 - 05:23 PM.

[formergenius]

There's also a webcast, as alex921 informed me. It's available for replay I believe, as it was live this morning, though you'd have to check.
See this article for further info. I'm hoping they release or hint at the structure within this presentation.. I'll check it out myself tomorrow.

[formergenius]

Hmm so the webcast didn't cover Naurex alas. Guess it's back to waiting.

[protoject]

Hmm so the webcast didn't cover Naurex alas. Guess it's back to waiting.

What if we just ask the company directly?
Probably a no-go but curious if anyone did it

[formergenius]

What if we just ask the company directly?
Probably a no-go but curious if anyone did it

I remember reading someone did, though I don't remember who. They never had a reply. I doubt they'd give up the structure to a random civilian without them signing a non-disclosure contract.

Edited by formergenius, 20 January 2014 - 10:20 PM.

[protoject]

I also doubt this, however I did email them claiming that I'm a student doing a research project , hopefully they bite onto that

BTW does anyone have a take on GLYX-13 VS Lanicemine in terms of pharmacological mechanism of action, difference in effects, and cost?

[formergenius]

"little to no psychotomimetic effects" vs. "no psychotomimetic effects" for one.
Antagonism has a whole array of reason why you wouldn't want to do it, whereas agonism seems to lack these properties.
GLYX-13 lasts much longer than Lanicemine, and has nootropic effects.

[typ3z3r0]

So today I decided to try find the structure for NRX-1074 again, but had no luck, just as in the past. However, I did come across "CERC-301", which seems promising too.

 

From the announcement regarding the phase 2 trial:

CERC-301 is a novel, potent and selective antagonist of the NMDA receptor subunit 2B (NR2B). It has the potential to be a first-in-class oral medication that is complimentary to existing treatments in patients with depression who have not adequately responded to their current therapy. These therapies are often limited by modest response rates, poor remission rates, slow onset of action and problematic side effects. In an exploratory proof-of-concept study published in 2012, CERC-301 demonstrated rapid antidepressant efficacy in patients with treatment resistant depression. Cerecor is conducting a 135 patient, placebo-controlled Phase 2 study of CERC-301 in this indication with results expected during the second half of 2014.

 

The drug was previously known as "MK-0657" (as can be seen in this article) when it was being studied by Merck, and the structure for it is listed in at least one patent, which I've inserted below.

 

Edited by typ3z3r0, 15 April 2014 - 01:40 AM.

[datrat]

I'm glad you found this. With your chemical background, would this be a hard one to synth?

[typ3z3r0]

LOL. Unfortunately, I am terrible with chemistry and have no idea. I've posted about it on reddit as well though, here, so we shall see what people reply with. I also found two other promising drugs, which, like CERC-301, are both orally active antagonists of the NMDA receptor subunit 2B. They are EVT 101 and EVT 103. You can view a rat study on 101 here and view its structure below (taken from this patent). According to this patent, it is 5-(4-fluoro-3-(difluoromethyl)phenyl)-3-((2-methyl-1 H-imidazol-1-yl)methyl)pyridazine. I can't actually find the structure for EVT 103, however.

 

 evt101.png   5.86KB   2 downloads

[tolerant]

Are Lanicemine and GLYX still being developed? I read somewhere that at least one of them has been abandoned...

[formergenius]

Are Lanicemine and GLYX still being developed? I read somewhere that at least one of them has been abandoned...

 

I doubt it's GLYX, so probably Lanicemine then. Though, abandoning GLYX in favour of NRX-1074 is not unimaginable.

[tolerant]

Is a group buy of GLYX-13 feasible?

[formergenius]

You're too late I'm afraid.. We already had a small one.

[tolerant]

You're too late I'm afraid.. We already had a small one.

 

And how would you sum up the results? 

[tolerant]

If anyone has any unwanted GLYX from the group buy, I would be happy to buy it from them...

[formergenius]

Dunno, I went unilaterally deaf and remained so one day after my second experiment, so I figured despite the small chance (deafness happened right after using eardrops) of GLYX being the culprit, I sure as hell can't afford to compromise any more of my senses. So, it's sitting in my fridge, dissolved. Had I not dissolved it all I could've parted with it, but it's basically useless now. I'm just going to wait until NRX-1074 is available, and until then just try other stuff.