Jump to content

Type II/III metabotropic glutamate agonists


Recommended Posts

If you haven't read this already, give it a read. I've read it a couple of times in the past, but the following caught my eye this time:

 

Both LY354740 and the type II/III metabotropic agonist (1S, 3S)-ACPD, which reduce the release of glutamate by acting on presynaptic inhibitory autoreceptors, are able to block excitation induced by 5-HT2A receptors in vitro (Marek et al, 2000).

Two positive sounding actions to me...

Look at the profile of LY354740 a.k.a Eglumegad:
 

 

Mechanism of action

Eglumegad acts as a group-selective agonist for the group II metabotropic glutamate receptors (mGluR2/3).[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 N-methyl-D-aspartic acid (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 5HT2A agonist hallucinogens,[17] while conversely the mGluR2/3 antagonist LY341495 increased the behavioural effects of these drugs.[18] This suggests that mGluR2/3 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 5HT2A 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]

 

 

 

A concern is that they appear to reduce dopamine.

AMPA or kainate glutamate antagonist also block 5-HT2a-induced release of glutamate.

 

Thoughts?

  • Upvote 3
Link to comment
Share on other sites

Going to read the first study before I give my comments, but Eglumegad seems highly intriguing. Particularly the information on its potential in psychosis and less significant (though still present) effects against PCP-induced dissociation (which I believe, alongside large doses of DXM, caused my HPPD and fear of even thinking about psychedelics (as though I have some hard core PTSD-like memories of psychedelic trips - it sucks because some of them were quite enjoyable!)). I'm sure there would be rather easy ways to bypass the decreased dopamine, though perhaps I'm wrong..

Link to comment
Share on other sites

Currently reading the glutamate paper - really fascinating read. One thing resonates with me: "Glycine is an ‘obligate co-agonist’ for glutamate, i.e. glutamate cannot act on the NMDA receptor in the absence of glycine. The simultaneous binding of the two transmitters and partial depolarisation permits Mg2+displacement and channel opening."

 

Recent research indicates glycine is a "semi-essential" amino acid that many may be moderately deficient in most people:

 

"Detailed assessment of all possible sources of glycine shows  that synthesis from serine accounts for more than 85% of the total, and that the amount of glycine available from synthesis, about 3 g/day, together with that available from the diet, in the range 1.5–3.0 g/day, may fall significantly short of the amount needed for all metabolic uses, including collagen synthesis by about 10 g per day for a 70 kg human."

 

"This result supports earlier suggestions in the literature that glycine is a semi-essential amino acid and that it should be taken as a nutritional supplement to guarantee a healthy metabolism"

 

This actually coincides with some other research, but I don't want to get off topic. The point being is that for even proper collagen synthesis we need about 10g/day of glycine (for someone around my size), let alone for optimal NMDA/gluatmatergic functioning. Cartilage and skin (not so much in the bones as most believe) of animals have a lot of glycine. 

Link to comment
Share on other sites

Some treat schizophrenia with megadose glycine.. like 50-60g/day IIRC. I think this is for theorised glutamatergic hypofunction, but I could be incorrect. I tried it a while back for HPPD but didn't get passed the first day as I couldn't be bothered with those doses. There should be some discussion about glycine in the 'Why NMDA antagonism' thread.

Edit:

http://www.ncbi.nlm.nih.gov/pubmed/9892253

Given your thoughts on your personal pathology, might be worth a trial for you. I have loads of powdered glycine I don't need if you want it.

Link to comment
Share on other sites

Sorry; I was in a hurry and didn't see it was Syntheso who posted. My bad!

BPC: I would look in to D-serine or Sarcosine as NMDAR co-agonists; those mega-doses of glycine make me nauseous, and I'm not one to get nauseous fast. Plus it's sweet, with a disturbing twist.
Preferably D-serine, as it is a full agonist.

About Eglumegad: The reduction of intracellular cAMP is quite interesting, as this would mean less CREB activation, which could exert beneficial effects on Dynorphin levels. (If I recall correctly; haven't spent too much time looking into those pathways). As for the reduction of dopamine levels: whether that would be beneficial or detrimental, would be dependant on the localization I suppose. It's interesting that a glutamatergic agonist is neuroprotective, rather than excitotoxic. I'm not sure how beneficial the reduction of glutamate would be.. I mean it does seem to be the working theory currently for DP (considering the Lamotrigine stuff), but I can't say I completely agree with this view. Nonetheless, still interesting.

Link to comment
Share on other sites

Some treat schizophrenia with megadose glycine.. like 50-60g/day IIRC. I think this is for theorised glutamatergic hypofunction, but I could be incorrect. I tried it a while back for HPPD but didn't get passed the first day as I couldn't be bothered with those doses. There should be some discussion about glycine in the 'Why NMDA antagonism' thread.

Edit:

http://www.ncbi.nlm.nih.gov/pubmed/9892253

Given your thoughts on your personal pathology, might be worth a trial for you. I have loads of powdered glycine I don't need if you want it.

Truthfully, I'd love that. Yet I wouldn't want to trouble you with sending me all of that, haha. 

 

Sorry; I was in a hurry and didn't see it was Syntheso who posted. My bad!

BPC: I would look in to D-serine or Sarcosine as NMDAR co-agonists; those mega-doses of glycine make me nauseous, and I'm not one to get nauseous fast. Plus it's sweet, with a disturbing twist.

Preferably D-serine, as it is a full agonist.

About Eglumegad: The reduction of intracellular cAMP is quite interesting, as this would mean less CREB activation, which could exert beneficial effects on Dynorphin levels. (If I recall correctly; haven't spent too much time looking into those pathways). As for the reduction of dopamine levels: whether that would be beneficial or detrimental, would be dependant on the localization I suppose. It's interesting that a glutamatergic agonist is neuroprotective, rather than excitotoxic. I'm not sure how beneficial the reduction of glutamate would be.. I mean it does seem to be the working theory currently for DP (considering the Lamotrigine stuff), but I can't say I completely agree with this view. Nonetheless, still interesting.

Thanks for the recommendations. I may look into those as I believe I've seen you speak about D-Serine before, and the information intrigued me, as did that on sarcosine. 

Link to comment
Share on other sites

Create an account or sign in to comment

You need to be a member in order to leave a comment

Create an account

Sign up for a new account in our community. It's easy!

Register a new account

Sign in

Already have an account? Sign in here.

Sign In Now
 Share

×
×
  • Create New...

Important Information

By using this site, you agree to our Terms of Use.