5-HT6 receptor potential?

[cybergollum]

Receptor: 5-HT6 (1993)

Function:
-Anxiety
-Cognition
-Learning
-Memory
-Mood

...the 5-HT6 agonists WAY-181,187 and WAY-208,466 have been demonstrated to be active in rodent models of depression, anxiety, and obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions.

Full agonists:
2-Ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT, 2-Et-5-MeO-DMT)

2-Ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT) is a tryptamine derivative which is used in scientific research. It acts as a selective 5-HT6 receptor agonist, with a Ki of 16 nM, and was one of the first selective agonists developed for this receptor. EMDT inhibits both short- and long-term memory formation in animal studies, and this effect can be reversed by the selective 5-HT6 antagonist SB-399,885. Additionally, it is active in the tail suspension test, suggesting that it could be an effective antidepressant.

Doesn't it look quite an exciting? I want to try it
Is there a possibility that other tryptamines has 5-HT6 affinity too? (upd: just found that there are at least DMT and LSD has 5-ht6 affinity). Or even not only triptamines but substituted amphetamines/phenethylamines too? I mean maybe scientists just didn't look for it because it was discovered later than 5-ht2 receptors (or this research had lower priority and/or seemed that it has lower therapeutic potential and/or there were no enough money) so there is now just a undiscovered field of possibilities. Or I'm misunderstanding something?

Btw, there is information on Wikipedia that 25i-nbome has it so probably other nbomes will have it too (and maybe even regular 2c-x, who knows?):

Receptor Ki (nM) ±
5-HT2A 0.044
5-HT2C 2
5-HT6 73 12
μ-opioid 82 14
H1 189 35
5-HT2B 231 73
κ-opioid 288 50

What is interesting too that 25i-nbome active on μ-opiod receptor. Am I the only one who didn't now this?
Ha, maybe that's why I used it quite a lot and liked it so much :D

Anyway, the question is: anyone knows (or have a theory/papers) how activation of this receptor alters the trip? And if there any theoretical profit from using substances (if there will be any on research drugs market) which are only active on 5-ht6 and not (or has low affinity) on other receptorts?

 

[serotonin2A]

Doesn't it look quite an exciting? I want to try it
Is there a possibility that other tryptamines has 5-HT6 affinity too? (upd: just found that there are at least DMT and LSD has 5-ht6 affinity). Or even not only triptamines but substituted amphetamines/phenethylamines too? I mean maybe scientists just didn't look for it because it was discovered later than 5-ht2 receptors (or this research had lower priority and/or seemed that it has lower therapeutic potential and/or there were no enough money) so there is now just a undiscovered field of possibilities. Or I'm misunderstanding something?

Btw, there is information on Wikipedia that 25i-nbome has it so probably other nbomes will have it too (and maybe even regular 2c-x, who knows?):

What is interesting too that 25i-nbome active on μ-opiod receptor. Am I the only one who didn't now this?
Ha, maybe that's why I used it quite a lot and liked it so much :D

Anyway, the question is: anyone knows (or have a theory/papers) how activation of this receptor alters the trip? And if there any theoretical profit from using substances (if there will be any on research drugs market) which are only active on 5-ht6 and not (or has low affinity) on other receptorts?

The data you cited with 25I-NBOMe show that it probably doesn't appreciably interact with 5-HT6. The Ki values were 0.044 nM for 5-HT2A and 73.12 for 5-HT6. Let's examine what would happen if 25I-NBOMe was present in the brain at a concentration of 1 nM. At that concentration, 95.7% of the 5-HT2A receptors would be occupied, but only 1.3% of the 5-HT6 receptors would be occupied. That probably isn't enough 5-HT6 occupation to produce any effect.

Likewise, some hallucinogens do have affinity for MOR, but it is too low relative to the 5-HT2A affinity to have a meaningful effect.

 

[cybergollum]

I see.

But you said "probably" so there still a possibility that even these 1.3% receptors could produce some noticeable effects. Anyway, I quoted 25i-nbome just like example. Maybe other well-known substances actually has higher affinity to 5-ht6. And btw why there usually (if any) information about activity only on 5-ht2 receptors for psychedelics and not 5-ht6? Is this because it is so unrecognizable and too low and scientists just don't want to put it value in papers? Or they just need equipment/money/time which they have not for finding it?

I am not really familiar with technologies and methods which used for research of that type, excuse me.

 

[roi]

What is interesting too that 25i-nbome active on μ-opiod receptor. Am I the only one who didn't now this?

Just look at the numbers, you'd have to take a far beyond lethal dose to notice any opioid effects at all.

 

[cybergollum]

People notice some effects even from homeopathy (=placebo) :D I am not saying that I felt opiod effects, I joked that I liked 25i-nbome because of them. So relax.

I just wanted to say that there is a huge lack of understanding (at least in my mind) how specific substances work because of gray zones like 5-ht6 (for example, as we are talking about it in this thread; there actually much more of such zones of course). And I would be glad if anyone provide me some abstracts or thoughts about 5-ht6 and its probable impact on effects you receive from psychedelics.

 

[adder]

Psychedelics differ in effects because they have different affinities at different 5-HT receptors and various 5-HT subtypes mediate various neurotransmitters release. 5-HT6 agonists facilitate GABAergic neurotransmission and that's likely the reason why they have anxiolytic properties in studies.

Anyway, I bet that psychoactive effects of psychedelics are mostly mediated through 5-HT1 and 5-HT2 subtypes (not counting super-selective NBOMe derivatives) and effects on other subtypes are secondary at best (mostly some tryptamines I guess).

 

[serotonin2A]

I see.

But you said "probably" so there still a possibility that even these 1.3% receptors could produce some noticeable effects. Anyway, I quoted 25i-nbome just like example. Maybe other well-known substances actually has higher affinity to 5-ht6. And btw why there usually (if any) information about activity only on 5-ht2 receptors for psychedelics and not 5-ht6? Is this because it is so unrecognizable and too low and scientists just don't want to put it value in papers? Or they just need equipment/money/time which they have not for finding it?

I am not really familiar with technologies and methods which used for research of that type, excuse me.

No, 25I-NBOMe would not have any opioid effects. There is no way that typical doses reach that level of 5-HT2A saturation. And 1.3% occupation of MOR is unlikely to do much of anything. At that level of 5-HT2A occupation you would probably be dead due to the dose of 25I-NBOMe ingested, but in any event you would be way too intoxicated to notice any opioid effects.

To answer your second question, scientists have tried to determine if 5-HT6 contributes to the effects of hallucinogens, but they haven't been able to identify any effects that are caused by those interactions. That is not unexpected, because there isn't much known about the role that 5-HT6 plays in serotonergic transmission.

 

[yaesutom]

I thought I read that DiPT and some of the other audio distorting tryptamines were strong 5-ht6 agonists?

 

[adder]

Do you mean this thread by any chance? Well, it's speculation, but who knows, it makes sense, so it's not impossible.

 

[blueberries]

I've been studying this for a while actually. With the right compounds in place, one could create a mixture that hits every nootropic target while countering the negative aspects of them (such as anxiety). HT6 is pretty great, HT3 & 4 are too, however one is an agonist, the other an antagonist. So you'd have to find selective agents for each compound along with more selective compounds to counter the negatives (and just the negatives). For instance benzos wouldn't work as they'd pretty much negate any anxiolysis there is, and of course the opposites of the selective ones wouldn't work. What I do like though is "a5IA". It's an inverse agonist at GABAa5, so it becomes a very effective nootropic. This compound also negates the negative effects that antagonists at GABA receptors would produce, like anxiety.

You have to remember though, along with seretonergic agents there will accompany a host of negative side effects. If you learn how to selectively negate these then you're winning. This does mean a lot of compounds in one however, or one compound that does everything (something I like to call "The Holy Grail"). The latter is nearly impossible but someday in the future someone will stumble upon it!

 

[Zeds(NCO2CH2CH3)2]

Many psychedelics have LOW 5HT6 activity, and many psychedelics haven't even been completely or correctly assayed for 5HT6 either because the receptor is "relatively new". 5HT6 agonists cause sound and some visual disturbances, but they seem more propagatory to 5HTx/5HT2x activities.

Someone I spoke to once tried a 5HT6 antagonist and from hearing that they claimed it caused the 3D-like saturation effect that psychadelics do(apparent lack of morphing visuals), but there was a feeling of emptiness, and a urge to smoke ziggs. Those 5HT6 antagonists in clinical trials are surely going to FAIL FAIL FAIL, they affect sound processing alot (active sound listening) not making you impossible to hear, but the analogy "in one ear, out the other" makes you much more spacier.

If you ask me there is this recurring trend of RC labs marketing the highest affinity 5HT2A/5HT1A compounds and ignoring ones with moderate affinity at many receptor subtypes, consider LSD this is a beautiful panacea of this. A degree of multiple receptor interaction is definitely required for true psychedelia and the concept of synesthesia is a combination of probably mainly 5HT2A/5HT1A, 5HT6 agonism, among a few other serotonin receptors, adrenergic, DA receptors etc.. Its wierd.. RC lab producers have been going in the completely opposite direction the whole time, sure we've obtained some pretty interesting examples of the known psychs that exhibit all that is outlined above(2c-X series, NbOME series, etc) but the original lets make "BENZOFURY", MDAT, Lets do MD-cathinones etc. Didnt work per say.
The new RC approach however is vetted in ALLAD and a few other derivs of actually knowns with binding assays that are broad, its come full circle, RCs are slowly NOT proving what they SHOULD BE, purported "replacements" they are entirely different. As they should be they are entirely different compounds.

You must think it to be peculiar and paradoxical that we are all exploring the analogues of psychedelics based on their euphoria effects, while big pharma utilizes computers to find analogues on therapeutical compounds for clinical effect, two different worlds?
This chasing of the psychedelic similarity is mind boggling, everything is right in its own aspect, there is no holy grail, there is no standard, there is no comparison, hell through further psychedelic usage, the remodeling causes effectively changes experiences, somewhat, so we are all not constant standards, not exactly sure what we are chasing, or if its the psychedelic chasing that is just insanity. IDK
zedsdead