LY-341,495: Group II Metabotropic Glutamate Receptor Antagonist

[SeenSoFar]

So everyone, as I was surfing Wikipedia aimlessly this fine afternoon, I came across a rather interesting compound. Allow me to quote a passage, and you all can see for yourselves why this compound and/or others with similar pharmacological activity should be closely examined by our community:

It is used in scientific research in several different areas, showing antidepressant effects in animal models, increasing the behavioural effects of hallucinogenic drugs in animal tests, and increasing the analgesic effects of μ-opioid agonists, as well as modulating dopamine receptor function.

It would seem that mGluR_2/3 play an intimate roll in the action of serotonergic psychedelics and μ-opioids. I would absolutely be interested in laying hands on this compound or one with similar properties, as I am very curious about it's ability to enhance or modify the psychedelic experience. It seems that this is not just a quirk of this particular compound either, but rather something intimately related to this receptor, since LY-379,268, which is an agonist at the same receptors, has the opposite effect:

LY-379,268 has sedative, neuroprotective, anti-addictive and anticonvulsant effects in animals, and blocks the effects of PCP and DOI, which has led to research into LY-379,268 and similar compounds as antipsychotic drugs for the treatment of schizophrenia.

Does anyone have any more information, or any thoughts on this? Perhaps this could be a whole new avenue for our community to explore. Perhaps it will be a way to increase the potency of our chemicals and thus make them go farther, or perhaps it will drastically modify the experience and create a whole new flavor to things.

 

[endotropic]

Perhaps it will be a way to increase the potency of our chemicals and thus make them go farther, or perhaps it will drastically modify the experience and create a whole new flavor to things.

Or perhaps it will morph a psychedelic experience into an anxious hell-trip. Rodent "psychedelic effects" are quantified by scoring head twitches, which seems more like a measure of psychedelic induced anxiety than an actual measure of psychedelia. Anxiety also has an antinociceptive effect, so that's consistent with the mu potentiation as well. I wonder if anyone has tested this with behavioral models of anxiety?

I'd love to hear a trip report on the combo, but I certainly wouldn't put myself forward to guinea pig.

 

[SeenSoFar]

Or perhaps it will morph a psychedelic experience into an anxious hell-trip. Rodent "psychedelic effects" are quantified by scoring head twitches, which seems more like a measure of psychedelic induced anxiety than an actual measure of psychedelia. Anxiety also has an antinociceptive effect, so that's consistent with the mu potentiation as well. I wonder if anyone has tested this with behavioral models of anxiety?

I'd love to hear a trip report on the combo, but I certainly wouldn't put myself forward to guinea pig.

You are absolutely right, it could be a negative change, absolutely. However, from what I know about the metabotropic glutamate receptors, and I could absolutely be wrong here, the binding of an AGONIST to these receptors can cause anxiogenesis and nociception. If this is indeed true, it follows that an antagonist would have anxiolytic and antinociceptive properties. Considering that glutamate is excitatory, this seems logical, although I don't know all that much about the MGluR, so I can't say for sure either way. I would appreciate for someone with knowledge of this particular receptor family to step in, if there is anyone.

 

[Katuskoti]

Psychedelics actually work through binding to 5-HT2A/mGluR2 receptor heterodimers and thusly exert their effects. I have been fascinated by metabotropic glutamate receptors and their ligands for the past several months. Look into eglumegad.

 

[SeenSoFar]

Psychedelics actually work through binding to 5-HT2A/mGluR2 receptor heterodimers and thusly exert their effects. I have been fascinated by metabotropic glutamate receptors and their ligands for the past several months. Look into eglumegad.

Thank you for reminding me about this fact. I was recently reading about this fact, and now that you have brought it back to the forefront of my mind, it is no surprise that agonists and antagonists at mGluR₂ exert effects on the psychedelic experience. All the more reason for us to explore this forthwith.

I've read about eglumegad. It is a group II agonist and acts to reduce the effects of serotonergic psychedelics. This is interesting from a pharmacological standpoint, but I am much more interested in the synergistic effects that are reported with an antagonist. I have a feeling in my gut that this could be the next major breakthrough in this field. We live in exciting times...

 

[FunctionalOlfactio]

I also spend hours researching many facinating chemicals on wikipedia. I identify with your interest and my ego clings to the similarity. Now I must overtly digress and lose myself in bland rambling. The nature of the mechanism of action of hyper-selective g-coupled protein receptor agonist which demonstrate selectivity at 5ht2a has lead to research in regards to some of the many plausible down stream effects related to the visual distortions involved in psychedelic experiences. The observation 5h2a selective antagonist block some of the symptoms of psychedelics in animal models is what lead research in this direction. Now I state something I remember well myself. Recreational psychedelics are less selective and have a multifaceted mechanism of action.



RISKING MY FREEDOM OBTAINING UNRESEARCHED HYPER-SELECTIVE AGONIST IS A WASTE OF MY TIME AND FREEDOM. THEY WILL LIKELY BE DANGEROUS, HAVE LITTLE RECREATIONAL VALUE, AND LITTLE THERAPEUTIC VALUE.




The most valuable psychedelics have binding at multiple locations and effect multiple systems. LSD is a good example. LSD has lower affinity at 5ht2a than several other sites and also has significant dopamanergic activity. The full psychedelic experience involves more than 5ht2a alone. Some of these more balanced psychedelics have equal potential in regards to self discovery too. I would pursue this more, but I know there will be some information on this forum towards the end of the year about an unscheduled molecule with similar effects to LSD that was created by Albert Hoffman and showed promising results during clinical human research about 50 years ago.

 

[SeenSoFar]

I think you have missed the point here... This is NOT a 5-HT2_A agonist. It is an antagonist at Group II of the metabotropic glutamate receptor family. Research has shown that co-administration of a serotonergic psychedelic and an mGluR_2/3 antagonist increases the behavioural effects of the psychedelic in animals... I'm well aware of the effects of selective 5-HT2_A agonists.

 

[endotropic]

You are absolutely right, it could be a negative change, absolutely. However, from what I know about the metabotropic glutamate receptors, and I could absolutely be wrong here, the binding of an AGONIST to these receptors can cause anxiogenesis and nociception. If this is indeed true, it follows that an antagonist would have anxiolytic and antinociceptive properties. Considering that glutamate is excitatory, this seems logical, although I don't know all that much about the MGluR, so I can't say for sure either way. I would appreciate for someone with knowledge of this particular receptor family to step in, if there is anyone.

That's good information. Coupled with the 5-HT2A/mGluR2 heterodimer hypothesis this might be more than just a pipe dream.