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[Sciencyst]

From Wikipedia

http://en.wikipedia.org/wiki/Eglumegad

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Eglumegad

Eglumegad (LY354740) is a research drug developed by Eli Lilly and Company, which is being investigated for its potential in the treatment of anxiety[1] and drug addiction.[2] It is a glutamate derived compound and its mode of action implies a novel mechanism.[3]

Mechanism of action

Eglumegad acts as a group-selective agonist for the group II metabotropic glutamate receptors (mGluR_2/3).^[4][5] It is unclear whether Eglumegad directly interacts with dopamine D2 receptors.^[6][7]
Effects

In experiments on mice, eglumegad was found to be as effective as diazepam for treating anxiety symptoms in several standard tests, but without producing any of the negative side effects of diazepam such as sedation and memory impairment.^[8] Tests in humans confirmed that it produced anxiolytic effects without producing sedation.^[9][10] However it did slightly reduce cognitive performance in tests on monkeys.^[11]
Eglumegad has also been found to be effective in relieving the symptoms of withdrawal from chronic use of both nicotine^[12] and morphine in animals,^[13] as well as inhibiting the development of tolerance to morphine,^[14] raising hope that this drug may be useful for treating drug addiction in humans.
Eglumegad and related drugs are neuroprotective^[15] and are synergistic with the neuroprotection produced by NMDA antagonist drugs,^[16] which may make these drugs useful in aiding recovery from brain injury.
This class of drugs also interacts with hallucinogenic drugs, with eglumegad reducing the effects of 5HT_2A agonist hallucinogens,^[17] while conversely the mGluR_2/3 antagonist LY341495 increased the behavioural effects of these drugs.^[18] This suggests that mGluR_2/3 agonists such as eglumegad may have potential uses in the treatment of some forms of psychosis, although eglumegad had only limited effects on the action of the dissociative drug phencyclidine^[19] which is generally a better model for schizophrenia than the 5HT_2A agonist hallucinogens.^[20]
Eglumegad also interferes in the hypothalamic–pituitary–adrenal axis, with chronic oral administration of this drug leading to markedly reduced baseline cortisol levels in bonnet macaques (Macaca radiata); acute infusion of eglumedgad resulted in a marked diminution of yohimbine-induced stress response in those animals.^[21]
In human adrenocortical cells, Eglumegad has been shown to down-regulate intracellular cyclic AMP (cAMP) and steroidogenesis, with a significant decrease in aldosterone and cortisol production.^[22]
Clinical development

Development of this drug is continuing, with several clinical trials completed and more planned.^[23] Poor oral bioavailability of the original formulation led to limited efficacy in the initial human trials,^[24] and so the prodrug form LY544344 is more likely drug candidate for further development.^{[25][26][27][28]}




LY-544,344

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This sounds pretty interesting.. I have been trying to find current glutamatergic racetams and ampakines which have similar pharmacology but it has been difficult to find much... I believe at least one paper mentioned piracetam's use as an antipsychotic and its affinity for MGluR II & III, but it failed to mention any specifics. I will try to dig up the studies again. I would love to find an easily available MGluR 2/3 agonist though!!

[socialpiranha]

There are a few being developed but nothing widely available yet, fenobam is a more likely find.

[Sciencyst]

Yeah I looked into fenobam earlier. Interesting but IIRC it is full of unwanted sides.

[socialpiranha]

yeah i've read different things in different places about the sides.

[mrd1]

"Piracetam appears to bind to Glu2 and Glu3 subunits of AMPA receptors, of which Aniracetam binds to Glu3 mostly; binding to Glu2 is a unique site for Piracetam.[20]" (examine) [ Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors ]

Unfortunately, I believe that mGlu2/3 receptors are entirely different class of glutamate receptors which deal more with modulating NMDA receptors. However, I could be mistaken.

But, it seems that LY544344 is actually an antagonist at the mGlu2/3 sites and this seems like a attempt to reduce the side effects of ketamine since it is well known to be able to elicit a antidepressant effect. Does anyone know what the difference is between a uncompetitive antagonist, noncompetitive antagonist at the nmda receptor and a mGlu2/3 antagonist?

[Sciencyst]

Thanks for that info.. It seems they mean mglurs but its confusing.

Idk what you mean with the ketamine thing, but no its actually an agonist

[mrd1]

I meant that it seems that LY354740 might be mediating its effects via acting a prodrug for LY544344. If LY544344 is a antagonist then it would make it seem like an attempt to improve on ketamine.

But, while I have absolutely nothing to prove this, perhaps it doesn't matter if it is acting as a agonist or antagonist because as long as its original compound or metabolite both lead to a increase in excitory signaling sufficient to induce changes at a cellular and molecular level.

Heres the confusion, I believe, I am assuming that ketamine causes its antidepressant effects via binding to the gaba interneurons paradoxically increasing excititory neurotransmission via an indirect modulation of the ampa receptors.

So, if its metabolite binds to the gaba interneurons even if it is a mglu 2/3 antagonist it could actually increase excititory signaling.

When talking about traditional antidepresants like prozac and zoloft, it has already been demonstrated how the addition of a 5-ht antagonist can actually paradoxically enhance the 5-ht agonism mediated signaling via acting on the autoreceptors Ex. zoloft + abilify, mitrazapine, or seroquel.

Therefore, maybe it is possible for LY354740 and its metabolite LY544344 to be paradoxically synergizing rather than counteracting eachother by exciting a increase in excitory neurotransmission via slightly different mechanisms. If this is the case, than it is possible that like ketamine this mediates an activation of mTOR1C then a cascade of events in the cell leading to a increase in BDNF release and TRKB receptors (which serve as receptor sites where BDNF is able to bind). As well as, a triggering of regulatory systems that may be turned on and help reregulate dysregulated brain systems. Another example of activating regulatory signaling mediating antidepressant effects are lithium carbonate and sleep deprivation which both may be atleast partly due to their actions at GSK3.


I apologize for the near gibberish. All of this stuff is awfully confusing and has very unfriendly terminology.

http://neurocritic.b...y-or-neigh.html this post has helped me try understand ketamine's mechanism of action.

Heres the picture I refer to when I am dealing with ketamine like compounds from www.paulmorrison.org.

[VERITAS INCORRUPTUS]

It appears compounds like Eglumegad, an mGluR2/3 agonist, and GLYX-13, a NMDA glycine binding site specific partial agonist act to regulate the glutaminergic system in a highly similar manner to the classical NMDA antagonist Ketamine.

The dominant downstream effect seem to entail potent neurogenesis, synpatogenesis, and related 'brain repair and remodeling'.

These are all in a sense attempts to improve on ketamine in the fashion that ketamine is the standard for rapid, potent, and long lasting remediation of depression and other psychological conditions, but of course has that nasty little bugger of causing 'unwanted' adverse effects. The improvement is not within degree of effectiveness, but within the elimination of the undesired adverse effects.

As well of course an oral agent would be most preferential from the standpoint of ease of administration. Hence GLYX-13 has a 'relative' in the works for clinical testing, NRX-1074, that is superior in potency and oral bioavailability; as well as LY544344, the oral prodrug format now being pursued within the Eglumegad platform.

[Sciencyst]

Eglumegad is like the opposite of ketamine and blocks the psychotomimetic effects of NMDA antagonists. GLYX-13 is more similar, albeit they have halted trials on it.

An mGluR 2/3 antagonist would be more similar to ketamine and the like.

The problem with NMDA antagonists is that they are highly neurotoxic through cholinergic mechanisms and can really screw up LTP.

[VERITAS INCORRUPTUS]

^
I did not hear they halted the trials. Do you have a link as I cannot locate such on the net in a quick search?

NMDA antagonists are not significantly neurotoxic at viable therapeutic dosage protocols. Ketamine can as well be administered with a concurrent benzodiazepine to prevent neurotoxicity. Ketamine has been shown to be highly effective for rapid, potent, and long-lasting efficacy with administrations that could be conducted free from significant neurotoxicity. It is the adverse effects of the dissociation and related that concern the medical community.

I apologized in saying they regulate in a highly similar manner; I meant to note within all their specific glutaminergic signalling there is a prevalence of neurogenesis and synaptogensis that is creating the desired positive effects.

[Sciencyst]

^ Aw shit, sorry, I meant to say they stopped trials on the closely related compound Lanicemine! Sorry for the false presumption, this is why I usually doublecheck my sources even if I think I remember them.. but I was too lazy today ): I mixed them up because I followed the Lanicemine link from the GLYX-13 Wiki page. (It's the only link under "See Also"

GLYX-13 luckily is indeed still in development. Furthermore it appears GLYX-13 is a partial NMDA agonist. Very interesting, I had thought before it was an antagonist, or at least a few articles comparing it to ketamine seemed to make it sound like an antagonist. Yet in the Wiki article it still hints that it is an antagonist when it talks about anti-nociception and ataxia. What the hell. Is it a partial agonist that displaces glycine and therefore has a slightly similar role to NMDA antagonists, or would this mean the claims on ketamine are contradicted? This is confusing.

And yes you are correct, NMDA antagonists are okay at low doses. The recreational doses seem to do harm.

Oh, okay, yeah they definitely all have similar mechanisms in terms of what systems they work through. As a whole, I think glutamatergic drugs are the future of medicine.

Edited by katuskoti, 28 March 2014 - 02:50 AM.

[formergenius]

GLYX-13 luckily is indeed still in development. Furthermore it appears GLYX-13 is a partial NMDA agonist. Very interesting, I had thought before it was an antagonist, or at least a few articles comparing it to ketamine seemed to make it sound like an antagonist. Yet in the Wiki article it still hints that it is an antagonist when it talks about anti-nociception and ataxia. What the hell. Is it a partial agonist that displaces glycine and therefore has a slightly similar role to NMDA antagonists, or would this mean the claims on ketamine are contradicted? This is confusing.

I have some of this in my fridge. Problem is, the same day that I used some (or was it the day after?) I became deaf in my left ear, and still am, so I've halted my trial until I rule out that it's sensorineural.
I was also confused by this partial agonist thing. I suggest reading the wiki entry on partial agonists which will explain how GLYX-13 functions as somewhat of a "conditional antagonist" as I was calling it.

[VERITAS INCORRUPTUS]

Conditional antagonist is a reasonably sound term FG.

In my estimation, partial agonist activity at the NMDA glycine site (GLYX-13) creates a form of biased agonist/conditional antagonist, or better shall we say functional antagonist, activity; this biased agonism/functional antagonism (as it resembles the effects of classical NMDAR antagonists, but with extreme specificity for brain repair/remodeling induction over any of the adverse effects seen with classical antagonists).

GLYX-13 is termed a glycine site specific functional partial agonist, but again, I believe due to how it elicits its effects it is functionally acting in line in an NMDA antagonist manner, sans the adverse effects due to a specificity of effect within the engagement of this receptor. Partial agonist activity at the glycine specific site renders an effect that is entails only the good portion of the effect of potent NMDA antagonists such as Ketamine.

I as well believe largely GluR2/3 agonists are doing much of the same. That is my point. These pathways of agonist activity at these glutaminergic receptor specific sites engage almost solely the 'good' portion of the glutaminergic/NMDA signalling and indeed are the future. This again was the main basis of my point

This is also why an mGluR2/3 agonist can partially block the negative effects of a classical NMDA antagonist. I would speculate GLYX-13 may have something of a similar effect here as well, though I do not believe such has been assayed. Note, GLYX has been fast tracked by the FDA, certainly not halted.

Oh, proposal for short-hand for GLYX-13/glycine site specific functional ligands? Gly-NMDAR?

Anyway, the nature of the Gly-NMDAR is complex (as well as we are understanding the nature of many pathways are far more complex than prior understood):
https://www.ttuhsc.e...medchem2003.pdf http://www.pnas.org/...2/6031.abstract

[VERITAS INCORRUPTUS]

I think I got this

Ketamine, as a prime example, through its specific antagonist activity, creates a sensitization/upregulation (perhaps even increases receptor density) within these binding sites, to wit to create a 'potentialized' highly potent agonist effect at these sites. GLYX-13 may as well be acting allosterically or within the same manner (as a co-agonist or somehow potentiator). This as well explains the rapid, yet long lasting effects through this potent upregulation. This glutaminergic signalling elicits potent brain repair/remodeling pathways.

The question is asked herein about that which relates to this paradox, in another contextual glutaminergic setting (study) http://www.mind-and-...-in-depression/

I'm just throwing this out quickly so it is not of course nearly some fully realized scientific treatise on this 'phenomena', but hopefully it makes sense and is largely accurate within its main assertions...certainly fodder for discussion

Well, you heard it here first

Edited by VERITAS INCORRUPTUS, 28 March 2014 - 04:09 PM.