Pharmacology Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs

[Psychestim]

https://pubs.acs.org/doi/10.1021/acschemneuro.2c00597

@Kaleida & @Xorkoth, our ARIADNE reports were cited in this paper lol. Anyway, a really good paper on SAR of ARIADNE analogs and their pharmacological characterization.

 

[Skorpio]

That is so cool!

Also its really neat to see the different g-protein pathways investigated.

 

[Psychestim]

Here's the full PDF for anyone interested.

That is so cool!

It is, I was so excited when I noticed it. I didn't even look for it either, I just stumbled across it and read all of our usernames in the reference section lol.

Also its really neat to see the different g-protein pathways investigated.

Yeah and they looked at very novel compounds like 4C-TFM, 4C-PR and 5C-D. Really cool stuff in there.

 

[paracelsius]

imho It is bullshit from Big Pharma (Bristol-Meyer &Co) trying cash-in on Psychedelics. I mean what it is the point of psychedelics hallucinogen? The Hallucinations. Tons of $$$$ is being spent lately trying come up with non-hallucinogenic 5HT2a agonists. It is a "scam" investor scam kind of like the biaised Mu opioid agonist that are not addicitve that was run couple of years ago. Lots of ppl made a killing$$$

Google this guy Roland Griffiths of Johns Hopskins U. This guy (with David Nutt in UK) credited for the entire psyhedelic renaissance. that guy is quite possibly the most knowledgable person on psychoactive pharmacology than anybody with some 55 years studying them. He keeps telling people: "80%+ of ppl who benefit clinically from psychedelic experience are the one who experience the so-called "hallucinations" Like stop smoking after psilocybin...
I mean Western Culture is having a hard time accepting this fact: "The "Hallucinations" ARE the Cure" get over it.

 

[fastandbulbous]

imho It is bullshit from Big Pharma (Bristol-Meyer &Co) trying cash-in on Psychedelics. I mean what it is the point of psychedelics hallucinogen? The Hallucinations. Tons of $$$$ is being spent lately trying come up with non-hallucinogenic 5HT2a agonists. It is a "scam" investor scam kind of like the biaised Mu opioid agonist that are not addicitve that was run couple of years ago. Lots of ppl made a killing$$$

Google this guy Roland Griffiths of Johns Hopskins U. This guy (with David Nutt in UK) credited for the entire psyhedelic renaissance. that guy is quite possibly the most knowledgable person on psychoactive pharmacology than anybody with some 55 years studying them. He keeps telling people: "80%+ of ppl who benefit clinically from psychedelic experience are the one who experience the so-called "hallucinations" Like stop smoking after psilocybin...
I mean Western Culture is having a hard time accepting this fact: "The "Hallucinations" ARE the Cure" get over it.

Not so much the 'hallucinations' as the overall psychedelic action, regardless of the degree of sensory distortions (remember reading that psychedelics would be better named illusinogen than hallucinogens, as very rare to get true hallucinations, unless a silly dose of psychedelic. Solanacae alkaloids are the true hallucinogens). Psychedelic activity seems to be more related to overloading the sensory input neural mechanism, than any hallucinations (same thinking as dissociatives. Dissociatives reduce sensory input to zero, so brain is just left with internal feedback loops. Psychedelics open the valve so wide that the brain is swamped with sensory input: so much that it just ignores it all. At least that's my take)

 

[fastandbulbous]

There are other psychedelics with bog all visual activity. I think it was Shulgin who described visuals from psychedelics, as just the wallpaper...

I think that possibly the 5HT2a receptor can be further subdivided and I bet (no evidence, just a hunch), that the further subdivision will be discovered by examining the 5HT2a receptors associated with the brain's group of visual cortex areas (MDA hallucinations are so diffetent from LSD, yet they are both 5HT2a agonist)

 

[paracelsius]

I think that possibly the 5HT2a receptor can be further subdivided and I bet (no evidence, just a hunch), that the further subdivision will be discovered by examining the 5HT2a receptors associated with the brain's group of visual cortex areas (MDA hallucinations are so diffetent from LSD, yet they are both 5HT2a agonist)

Possible but I think the most important thing is selectivity among the different 5HT2aRs for a given compound. very few compounds will target 5HT2a alone: they will all pretty much affect 5HT1a, 2C and others like 5HT6R or 7R either partial or full agonist or antagonist. Each one has his know psychoactive response.. so you can imagine the spectrum of psychoprofile since there are some 14 different 5HTRs not all in the brain but still..

example:5HT1a agonists are serenics, antidepressant, aphrodisiac, anorexic and iirc there were a swedish study showing that activating them give a subjective "mystical religious experience". so is a 5HT2a agonist with also 1A agonist activity more likely to give that "mystical religious experience"? well those guys found selective 5HT1a do that their hypothesis anyway...

2Cs are opposite to 2As. 5HT2C agonist will antagonize 2A activation. So I think it is the spectrum of compound activity on different 5HT that gives overall psychoactivity depending on the compound selectivity.... but it could be 5HTa functional agonism/brain location or just 5HT2AR subtypes in the brain that ppl just dont know about yet. who knows?

To make matter more complicated, tryptamines for example are also releaser of serotonin with different potency.. DMT is actually quite potent serotonin releaser.

The brain is a very complicated piece of machinery.. how do Nature manage to get here, I do not know.

 

[fastandbulbous]

Isn't the 1a receptor where buspirone acts?

 

[fastandbulbous]

Possible but I think the most important thing is selectivity among the different 5HT2aRs for a given compound. very few compounds will target 5HT2a alone: they will all pretty much affect 5HT1a, 2C and others like 5HT6R or 7R either partial or full agonist or antagonist. Each one has his know psychoactive response.. so you can imagine the spectrum of psychoprofile since there are some 14 different 5HTRs not all in the brain but still..

example:5HT1a agonists are serenics, antidepressant, aphrodisiac, anorexic and iirc there were a swedish study showing that activating them give a subjective "mystical religious experience". so is a 5HT2a agonist with also 1A agonist activity more likely to give that "mystical religious experience"? well those guys found selective 5HT1a do that their hypothesis anyway...

2Cs are opposite to 2As. 5HT2C agonist will antagonize 2A activation. So I think it is the spectrum of compound activity on different 5HT that gives overall psychoactivity depending on the compound selectivity.... but it could be 5HTa functional agonism/brain location or just 5HT2AR subtypes in the brain that ppl just dont know about yet. who knows?

To make matter more complicated, tryptamines for example are also releaser of serotonin with different potency.. DMT is actually quite potent serotonin releaser.

The brain is a very complicated piece of machinery.. how do Nature manage to get here, I do not know.

4 billion years of evolution via trial & error. Like trying to understand how a VHS videorecorder works, purely by seeing videocassettes played...

 

[ecstacylover]

Possible but I think the most important thing is selectivity among the different 5HT2aRs for a given compound. very few compounds will target 5HT2a alone: they will all pretty much affect 5HT1a, 2C and others like 5HT6R or 7R either partial or full agonist or antagonist.

Even if you restrict yourself to looking at the 2A receptor, there's probably enough signaling diversity there to account for many of the subjective differences between psychedelics. For example, Gq activation within pyramidal neurons will deplete PIP2, which will excite these neurons via inactivation of KCNQ channels. However, Gq activation will also activate calmodulin which can substitute for PIP2 at these channels. Due to cross-talk with arrestin and other G protein pathways, each 2A agonist will have its own unique ratio of PIP2 depletion to calmodulin activation, resulting in a unique modulation of these channels.

Another example is HCN channels, which are among the most important regulators of pyramidal neuron excitability. These channels are modulated by PIP2, cAMP, and arachidonic acid, the levels of which will be influenced to differing degrees by different 2A agonists. These ion channels and others are also modulated by phosphorylation, and different 2A agonists will activate kinases to differing degrees. Different patterns of 2A-mediated gene regulation may also contribute to qualitative differences in the late phase of the experience.

 

[paracelsius]

Isn't the 1a receptor where buspirone acts?

Correct. Buspirone is a 5HT1A agonist prescribed as antidepressant. Incidentally it has priapism as side-effects in males and even more “turn-on” for ladies. 5HT1a agonists are quite interesting class: antidepressant + aphrodisiac + anorectic + serenics (anxiolytic) at the same time! In other words: just relax, get a boner (or super wet for ladies) with no worries of any kind and you and your partner enjoy yourselves. That is why it is used off-label for “female sexual dysfunction” euphemism for female aphrodisiac, right?!!

.....there were a swedish study showing that activating them give a subjective "mystical religious experience".......

Oh my mistake I take that back: it is actually 5H1A antagonist in that study that gives so-called “mystical, egoless, surrounded by God and Angels...etc” psychedelic experience. Not agonists as I mentioned. Makes more sense tho: last thing you want happen is gettin a boner (or aroused super wet) while you sittin there “surrounded by Angels”!! I guess Nature thought about that one and make sure it is the 1A antagonists that gets you close to "God and Angels" and the agonists make you relax, happy and...euhhh horny!

Even if you restrict yourself to looking at the 2A receptor, there's probably enough signaling diversity there to account for many of the subjective differences between psychedelics....

True. Downstream signalling after receptor activation can make a difference on subjective effect not only for 2A but other HTRs as well. Functionally selective agonists will have different effects than non-selective or at least some effects will likely be absent. Like opioids that I mention: MOR agonism leads to beta-arrestin pathway activation or cAMP pathways or both depending on the agonist selectivity. So things like morphine (non-selective MOR) activate both, outcome: analgesia, euphoria but also addiction, respiratory depression..etc. Beta-arrestin selective MOR agonists lack respiratory depression (iirc) but have similar analgesia. Euphoria? I dont know (it is pretty hard to ask rats if they feeling euphoric!). But still a potent MOR agonist analgesic even if addictive with no respiratory depression is quite interesting because respiratory depression is what kill when ODing on OPs right?

I have yet to see the psychoative effects of functionally selective 5HT2A agonists (or just plain compounds that are functionally selective). Problem tho it is very difficult to have pure 5HT2a agonists that do not affect other 5HTs. Would be interesting tho. I've read claims somewhere that you can make non-hallucinogenic 5HT2a this way, by biasing toward one or another signalling but I doubt they be useful therapeutic as I mention previous post but who knows?

4 billion years of evolution via trial & error. Like trying to understand how a VHS videorecorder works, purely by seeing videocassettes played...

At least with VHS it will work anywhere anytime (morning, afternoon, nite..etc), any mood (if it can have one!) pretty much the same way everytime so one can eventually figure how it works (not obvious but doable right?). not so with the brain...

Not only what is happening right now (in terms of brain activity receptors, transporters, pathways....etc) is different from what happened when you just woke up in the morning, and whether it is happening while you are at your home or another location but also whether at that very moment you feel good, sad, horny, anxious...etc (set-and-settings!).. Because, you see each of these factors will affect not only seretonergic but also other brain system ie dopaminergic, adrenegic, cholinergic...etc each with its own set of complexity like dopamine D1-D2, D5...post and presynaptic, brain distribution..I dont want even go there!

wait there is more: with psychedelics not only you’d have to deal with selectivity for all those 5HTRs (partial or full agonist, antagonist, reverse agonist..etc) and functional selectivity for each one, but you also have to deal with pre-synaptic autoreceptors activation especially with 5HT1A. See: some compound will be agonist at one set of autoreceptors (indirect antagonist ie inhibit release of 5HT) and agonist at other...

Which is why I believe so-called AI (artificial intelligence) will never get close to actual human brain! Can it “hallucinate”? or dream (well...same thing)? You tell me!

No wonder as you mention it took Nature 4 billion years of evolution to get here. The complexity of the human brain is quite mind boggling (no pun).

 

[fastandbulbous]

Understanding the human brain was never going to be easy, but it's the gradual elucidation that's the goal. I always compare it in effort required etc (no, not complexity!) to that required by the people at Bletchley park, decrypting Enigma machines in WW2, purely by monitoring radio broadcasts

 

[ecstacylover]

True. Downstream signalling after receptor activation can make a difference on subjective effect not only for 2A but other HTRs as well. Functionally selective agonists will have different effects than non-selective or at least some effects will likely be absent.

5-HT2A stands out in that it doesn't just activate Gq and arrestin, but can also activate G12/13, Gi, and Gs. The activation of non-canonical G proteins is likely downstream of either Gq or arrestin, as the Roth lab used BRET experiments to show 5-HT2A couples only to Gq-family members (along with a weak coupling to Gz).

I have yet to see the psychoative effects of functionally selective 5HT2A agonists (or just plain compounds that are functionally selective). Problem tho it is very difficult to have pure 5HT2a agonists that do not affect other 5HTs. Would be interesting tho. I've read claims somewhere that you can make non-hallucinogenic 5HT2a this way, by biasing toward one or another signalling but I doubt they be useful therapeutic as I mention previous post but who knows?

The Gonzalez-Maeso lab suggested that LSD activates the Gi pathway while non-psychedelic 2A agonist lisuride does not. Furthermore, there's data suggesting that psychedelic 2A agonists activate the Gs pathway while non-psychedelic 2A agonists lisuride and tabernathalog don't.

Although there's been so much research into functional profiles of 2A agonists and it's still quite unclear which pathways (or ratio thereof) are most relevant, and the expression system is often not constant across experiments. Personally I'd be much more interested to see electrophysiology of pyramidal cells studied for all the different 2A agonists, because then you could see which ion channels are being modulated in a native system and how the ion channel fingerprint varies across the different psychedelic 2A agonists.

 

[Fertile]

Not so much the 'hallucinations' as the overall psychedelic action, regardless of the degree of sensory distortions (remember reading that psychedelics would be better named illusinogen than hallucinogens, as very rare to get true hallucinations, unless a silly dose of psychedelic. Solanacae alkaloids are the true hallucinogens). Psychedelic activity seems to be more related to overloading the sensory input neural mechanism, than any hallucinations (same thinking as dissociatives. Dissociatives reduce sensory input to zero, so brain is just left with internal feedback loops. Psychedelics open the valve so wide that the brain is swamped with sensory input: so much that it just ignores it all. At least that's my take)

That really should be in a textbook ;-)

Tell it like it is!

 

[HOOH]

Oh my mistake I take that back: it is actually 5H1A antagonist in that study that gives so-called “mystical, egoless, surrounded by God and Angels...etc” psychedelic experience. Not agonists as I mentioned. Makes more sense tho: last thing you want happen is gettin a boner (or aroused super wet) while you sittin there “surrounded by Angels”!! I guess Nature thought about that one and make sure it is the 1A antagonists that gets you close to "God and Angels" and the agonists make you relax, happy and...euhhh horny!

what the hell are you talking about

5-MeO-DMT, perhaps the most potent "entheogen" is primarily a 1A agonist... I also have no idea what you are talking about with 1A agonists causing horniness, I believe it's the opposite

 

[fastandbulbous]

That really should be in a textbook ;-)

Tell it like it is!

Find me a publisher and I will make it so!

It's telling it like it is, that has caused virtually every employment problem I've ever had (well that and having some arsehole somewhere up the chain of command!)

 

[Fertile]

There are other psychedelics with bog all visual activity. I think it was Shulgin who described visuals from psychedelics, as just the wallpaper...

I think that possibly the 5HT2a receptor can be further subdivided and I bet (no evidence, just a hunch), that the further subdivision will be discovered by examining the 5HT2a receptors associated with the brain's group of visual cortex areas (MDA hallucinations are so diffetent from LSD, yet they are both 5HT2a agonist)

i think it is already inferred. The effectors differ with brain region via second messenger compounds.

 

[paracelsius]

5-HT2A stands out in that it doesn't just activate Gq and arrestin, but can also activate G12/13, Gi, and Gs. The activation of non-canonical G proteins is likely downstream of either Gq or arrestin, as the Roth lab used BRET experiments to show 5-HT2A couples only to Gq-family members (along with a weak coupling to Gz).


The Gonzalez-Maeso lab suggested that LSD activates the Gi pathway while non-psychedelic 2A agonist lisuride does not. Furthermore, there's data suggesting that psychedelic 2A agonists activate the Gs pathway while non-psychedelic 2A agonists lisuride and tabernathalog don't.

Although there's been so much research into functional profiles of 2A agonists and it's still quite unclear which pathways (or ratio thereof) are most relevant, and the expression system is often not constant across experiments. Personally I'd be much more interested to see electrophysiology of pyramidal cells studied for all the different 2A agonists, because then you could see which ion channels are being modulated in a native system and how the ion channel fingerprint varies across the different psychedelic 2A agonists.

That is right. As far as 5HT2A functional selectivity and “hallucinogenic” effects are concerned, it seems G-pathway but not beta-arrestin is required, so far as “hallucinogenic effects” are assessed by the standard head-twitch response in rodents. The problem is which downstream signalling is involved PIP or cAMP or whether selectivity for activating one or the other is relevant to the head-twitch. Kind of complicated: locarserin, the weight loss drug actually activate (full agonist 2a – cAMP downstream pathway) but it is not “hallucinogenic”! Does that mean PIP is the one responsible for “hallucinogenic” effects? what about other effects like anxiolytic (or anxiogenic) antidepressant ..etc of 2A agonists like psilocybin

The point I was trying to make is that it is very very difficult to have selective CNS drug that affect only one single receptor let alone one specific downstream (PIP v cAMP) signalling of one specific canonical pathway (G v beta-arrestin) of that receptor. The only few psychoactive I’ve come across that are extremely selective for one receptor is dissociative salvia mint plant compound Salvinorin A (this compound affect only and only opioid kappa receptors and nothing else in the brain by a 1 to 1000 margin! Incredible). Whether it is also functionally selective, I do not know.

The other one is a piperazine 4-(3-chlorophenyl)-1-phenethylpiperazine 3c-PEP incidently discussed here on BL when I tried googling it. Quite simple compound but It is an extremely selective dopamine reuptake inhibitor about 10000 more potent than cocaine and doesnt affect anything else, by 1 to 1000 margin at least!!).

I’ve seen ppl trying tease out “the hallucinations” of 2A agonism without affecting other good effects like antidepressant...etc (which the OP paper claim). Like with tabernanthologs of dave olsen or the work of Gonzalez-Maeso or also Scott Thompson in maryland. Sure 2A is required for head-twich (ie “mice hallucinating”) but not required for antidepressant. Shown by using either 2a KO rodents or a 2a antagonist... now dave olsen claims synaptogenesis resulting from brain grow factors BDNF stimulation (ie grow rat brain and make’em smarter and stop worrying!!) of tabernanthologs or other non-hallucinogenic tryptamines like 6-MeO-DMT as mechanism of AD. btw do rats worry sometimes?? Like telling themselves: “wait a min! the cat might be coming home soon, what do I do?” and finding there is no escape get depressed? Wish rats can talk..

joke aside tho, as I mention you have lots of other targets your 2A agonist might hit and lead to AD or anxiolytic response...etc Like take DMT it is a 5HT2a agonist but also a releaser of serotonin ie indirect non-selective agonist of all 5HTs since it increase the natural agonist!! well that is very interesting topic... grateful to have learn something today.

what the hell are you talking about

5-MeO-DMT, perhaps the most potent "entheogen" is primarily a 1A agonist... I also have no idea what you are talking about with 1A agonists causing horniness, I believe it's the opposite

I am talking about this..

• Fernández-Guasti A, Rodríguez-Manzo G (January 1997). "8-OH-DPAT and male rat sexual behavior: partial blockade by noradrenergic lesion and sexual exhaustion". Pharmacology, Biochemistry, and Behavior. 56 (1): 111–6. doi:10.1016/S0091-3057(96)00165-7. PMID 8981617. S2CID 26063338.
• Haensel SM, Slob AK (July 1997). "Flesinoxan: a prosexual drug for male rats". European Journal of Pharmacology. 330 (1): 1–9. doi:10.1016/S0014-2999(97)00170-2. PMID 9228408.

re: horniness it is kind of complicated. Buspirone is actually a 2A presynaptic autoreceptor agonist not post-synaptic 1A so yeah in that sense it is an indirect antagonist. but 8-OH-DPAT is a full agonist.. (hmmm that paper above: what they mean by "sexual exhaustion" of rats: hump hump hump till it drop??)

and this :

• Jacqueline Borg; Bengt Andrée; Henrik Soderstrom; Lars Farde (November 2003). "The Serotonin System and Spiritual Experiences". American Journal of Psychiatry. 160 (11): 1965–1969. doi:10.1176/appi.ajp.160.11.1965

re: "5HT1A activation and God and Angels...."

"..what the hell...." : now, we dont have to be in “hell” to debate. Been there believe me and I don’t want go back. If you ever been homeless in downtown vancouver east side, you’d know what I am talking bout. but that is another issue..

oh btw: 5-MeO-DMT is not the "most potent" entheogen. 5-MeO-NET is : Sasha Shulgin actually mention the unsubstituted NET as the "only++++ . but 5-MeO-NET is even more potent than NET which is more potent than 5-MeO-DMT..considering how easy to make from simple walmart melatonin, I wonder why it hasnt gotten ppl attention, I mean 5-MeO-NET.. but again this is another topic

Find me a publisher and I will make it so!

It's telling it like it is, that has caused virtually every employment problem I've ever had (well that and having some arsehole somewhere up the chain of command!)

hmmm who need a publisher when you have amazon e-book.. my former wife made a lots $$ just puttin a simple pharmacy undergraduate text she put together from her TAs years. I laughed her off her thinking wadda a waste ot time till we saw money rolling and the laugh was on me. you'd be amazed how these things work in this day and age when the entire world are your potential readers!

Happy Tuesday

 

[HOOH]

I am talking about this..

• Fernández-Guasti A, Rodríguez-Manzo G (January 1997). "8-OH-DPAT and male rat sexual behavior: partial blockade by noradrenergic lesion and sexual exhaustion". Pharmacology, Biochemistry, and Behavior. 56 (1): 111–6. doi:10.1016/S0091-3057(96)00165-7. PMID 8981617. S2CID 26063338.
• Haensel SM, Slob AK (July 1997). "Flesinoxan: a prosexual drug for male rats". European Journal of Pharmacology. 330 (1): 1–9. doi:10.1016/S0014-2999(97)00170-2. PMID 9228408.

re: horniness it is kind of complicated. Buspirone is actually a 2A presynaptic autoreceptor agonist not post-synaptic 1A so yeah in that sense it is an indirect antagonist. but 8-OH-DPAT is a full agonist.. (hmmm that paper above: what they mean by "sexual exhaustion" of rats: hump hump hump till it drop??)

Interesting, well, I don't know too much on this topic, but I will say that Buspirone is a 1A presynaptic agonist (as well as a "regular" 1A agonist), and other serotenergic drugs (most notably SSRIs) are known to be anaphrodisiacs. I can't comment too much on 8-OH-DPAT, but

• DOI: 10.1016/s0006-8993(98)00065-1

says the following:
"Serotonin (5-HT) is generally inhibitory to male rat sexual behavior. However, the 5-HT1A agonist 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), injected either systemically or into the medial preoptic area (MPOA), facilitates ejaculation"
as well as:
"Instead, the facilitative effects of 8-OH-DPAT in the MPOA on male copulatory behavior may result, at least in part, from stimulatory effects of 8-OH-DPAT on DA transmission"

Personally I would be a little surprised if it's dopaminergic effects can "override" the serotonergic ones, but who am I to argue with these researchers.

• Jacqueline Borg; Bengt Andrée; Henrik Soderstrom; Lars Farde (November 2003). "The Serotonin System and Spiritual Experiences". American Journal of Psychiatry. 160 (11): 1965–1969. doi:10.1176/appi.ajp.160.11.1965

re: "5HT1A activation and God and Angels...."

"..what the hell...." : now, we dont have to be in “hell” to debate. Been there believe me and I don’t want go back. If you ever been homeless in downtown vancouver east side, you’d know what I am talking bout. but that is another issue..

That study is a little interesting, I wouldn't say that the binding potential of a 1A antagonist (which has other targets as well) is too indicative of anything really. The conclusion "that the several-fold variability in 5-HT1A receptor density may explain why people vary greatly in spiritual zeal" is a little laughable and hints a bit at Reddit-style smug atheism. You (nor any paper for as far as I know) still haven't explained the entheogenic power of 5-MeO-DMT — a potent 1A agonist in any case.

oh btw: 5-MeO-DMT is not the "most potent" entheogen. 5-MeO-NET is : Sasha Shulgin actually mention the unsubstituted NET as the "only++++ . but 5-MeO-NET is even more potent than NET which is more potent than 5-MeO-DMT..considering how easy to make from simple walmart melatonin, I wonder why it hasnt gotten ppl attention, I mean 5-MeO-NET.. but again this is another topic

Do you have anything to back this up with? In TiHKAL, Shulgin notes on the entry for DET that both DET nad DiPT are "yet to have any active levels discovered", and also says that:

"Fourthly, and most important, every one of these adventures has an exact counterpart with the inclusion of that magical 5-methoxy group. Whatever is found with the 5-H archetype is certain to be more potent, and correspondingly unpredictable, with a 5-methoxy-substituent. Some have already been made. Most have not. This is open territory. Go west, young man"

Nowhere is 5-MeO-NET explored, nowhere is NET shown to be significantly active, neither of which are the "only ++++" — the only ++++ report I have found is for — wait for it — 5-Meo-DMT (which for all intents and purposes can be referred to as the most potent entheogen, even if that's a bit informal)

 

[Skorpio]

Whether it is also functionally selective, I do not know.

https://www.science.org/doi/10.1126/scisignal.aai8441

Here's a random paper about the design of non-dysphoric kappa agonists for itch. It goes into the g-protein pathways for dysphoria (although it may be a jump to correlate dysphoria with dissociative effects as dynorphins mediate dysphoria in humans endogenously in response to stress, but don't cause salvia type tripping).