6-fluoro-dmt

[Psychonautical]

6-Fluoro-DMT possess affinity for the 5-HT1A (392.6 nM), 5-HT1B (217.7 nM), 5-HT1D (55.4 nM), 5-HT1E (460.8 nM), 5-HT2A (866 nM), 5-HT2B (29.8 nM), 5-HT2C (674.2 nM), 5-HT5A (960.5 nM), 5-HT6 (25.6 nM), 5-HT7 (40.8 nM), D1 (547.3 nM), D2 (610.4 nM), D3 (866.8 nM), D4 (1,454 nM), D5 (6,291 nM), α1A-adrenergic (173.3 nM), α2B-adrenergic (295.5 nM), α2C-adrenergic (148.8 nM), H1 (46.6 nM), H2 (925.4 nM), I1 (898.4 nM), 1 (6,892 nM), and 2 (7,128 nM) receptors, as well as the SERT (144.6 nM).[1] It has low/negligible (> 10,000 nM) affinity for the 5-HT3, α1B-adrenergic, α2A-adrenergic, β1-adrenergic, β2-adrenergic, H3, H4, and M1-M5 receptors, as well as the DAT and NET.[1] It has not been screened at 5-HT1F, 5-HT4, α1D-adrenergic, β3-adrenergic, or VMAT1/VMAT2.

That is fucking horrifying.

 

[Thanatos]

Sounds like psychedelic death incarnate. I would touch this under any circumstance.

 

[188thStreet]

What do you think the effects would be like? I don't know enough to be able to speculate on subjective experience just based on the receptor binding. This is the first 6-substituted DMT analogue I've heard of.

 

[Thanatos]

I'm not a pharmacologist, I suggest you ask Ebola, Sekio, or Solipsis to chime in.
The histamine and adrenal effects scare me as far as psychedelics go.

Edit: no significant sigma agonism has been reported, unlike DMT proper? Please provide a citation for the ki values/binding affinity.

 

[Diode]

Could anyone possibly even elaborate slightly on what sort of effects we'd see from this kind of receptor activity?
is there a URL that holds a database of the receptor activity of various psychedelic similar to the OP?

 

[tryp2fun]

And yet, in TIHKAL Shulgin says 6-fluoro-DET was found to be inactive as a psychedelic at doses up to 100 mg IM.

 

[Thanatos]

^ the pharmacological effects between the 5-6 positional counterparts of the base tryptamines vary widely without much of a pattern. Shulgins data/opiniom is completely outdated in my opinion. Science has progressed leaps and bounds since those trials were conducted, and many substances where only bioassed a handful of times before the publishing of pihkal and tihkal.
Let's not get too caught up in Sasha's opinions.

 

[Psychonautical]

I have to say i'd imagine it would feel like all the lights are on, and no one is home.
Where ever "you" go.
Lets just hope the hardware is in a good enough piece to accept you back.

 

[Thanatos]

I wonder if this compound could precipitate seratonin syndrome by itself seeing as its not only a 5HT a-b agonist as well as exibiting SERT, DAT, and NET action?

Reading those binding profiles really makes me feel il-equipped to extrapolate pharmacological action just from a simple listing of ki values.

 

[Psychonautical]

It's just the sheer number. If you take a look at traditional psychedelics, its generally only a few receptor sites.

This just seems extreme. Like thats way way way more receptor binding sites than even those poisonous Nbome compounds.

I do imagine that you can reach a higher affinity, if wreckless doses were taken....
I wouldn't want to imagine maxing this substance out.
IF, it had any psychedelic effects.

Apparently 6-fluoro-Amt is a righteous beast.
However there hasn't really been any true pharmacological discussion done about it.

 

[buildersoftime]

But LSD binds to loads of receptors too right? Nichols calls it 'promiscuous pharmacology'.

 

[Psychonautical]

LSD affects a large number of the G protein-coupled receptors, including all dopamine receptor subtypes, and all adrenoreceptor subtypes, as well as many others.[citation needed] Most serotonergic psychedelics are not significantly dopaminergic, and LSD is therefore rather unique in this regard. LSD's agonism of D2 receptors contributes to its psychoactive effects.[80][81] LSD binds to most serotonin receptor subtypes except for 5-HT3 and 5-HT4. However, most of these receptors are affected at too low affinity to be sufficiently activated by the brain concentration of approximately 10–20 nM.[82] In humans, recreational doses of LSD can affect 5-HT1A (Ki=1.1nM), 5-HT2A (Ki=2.9nM), 5-HT2B (Ki=4.9nM), 5-HT2C (Ki=23nM), 5-HT5A (Ki=9nM [in cloned rat tissues]), and 5-HT6 receptors (Ki=2.3nM).[1][83] 5-HT5B receptors, which are not present in humans, also have a high affinity for LSD.[84] The psychedelic effects of LSD are attributed to its strong partial agonist effects at 5-HT2A receptors as specific 5-HT2A agonists are psychedelics and largely 5-HT2A specific antagonists block the psychedelic activity of LSD. LSD exhibits functional selectivity at the 5-HT2A and 5HT2C receptors in that it activates the signal transduction enzyme phospholipase A2 instead of activating the enzyme phospholipase C as the endogenous ligand serotonin does.[85] Exactly how LSD produces its effects is unknown, but it is thought that it works by increasing glutamate release in the cerebral cortex[82] and therefore excitation in this area, specifically in layers IV and V.[86] LSD, like many other drugs, has been shown to activate DARPP-32-related pathways.

Many many less binding sites, and much lower affinity

 

[Thanatos]

LSD ki value graph via Wikipedia

 

[lenses]

Flouride and florines need to stay as far away from DMT as possible.

This underlines how important clean water is in production of tryptamines. I could see contaminated water making contaminated DMT products, ALA the pathways of 5-Br-DMT.

Terrifying. Make that flouride SiF group and you're done with.

 

[Thanatos]

Are you posturing that 6-flourosilicic-dimethyltryptamine would be toxic?

 

[bloodshed344]

I want some of this stuff. Also, it said it had negligible NET and DAT action entheo, unless I'm seeing something wrong.

But I think you guys are just looking too deep into this without some actual qualitative reports.

 

[buildersoftime]

LSD affects a large number of the G protein-coupled receptors,
.
.
Many many less binding sites, and much lower affinity

Ok. So pharmacology isn't my forte but I can't see how this is horrifying/death incarnate. It binds to a whole load of seretonin, adrenaline and dopamine receptors but so does LSD. The main difference I can see is affinity to Imidazoline 1 receptors which means that we can expect the compound to act as an antihypertensive. A powerful psychedelic with less chance of causing anxiety and vasoconstriction sounds great to me.

Also you know that higher ki values mean lower affinity right? It looks like LSD has 2 orders of magnitude greater affinity to many receptor subtypes.

It's just the sheer number. If you take a look at traditional psychedelics, its generally only a few receptor sites.

This just seems extreme. Like thats way way way more receptor binding sites than even those poisonous Nbome compounds.

I'm not sure this argument works. NBOMes are know for their particularly high degree of selectivity. In other words they only bind to a very limited number of receptors.

Am I missing something? I've no idea what '1' and '2' receptors are referring to at the end of the list. Are these super evil or something? Or is the concern that the compound's relatively high H1 agonism could cause anaphylaxis?

I wonder if 6-C-DMT, 6-B-DMT and 6-I-DMT would share a similar SAR? Fluorine doesn't always act too much like a halogen in ring substitutions right?

 

[tryp2fun]

^ the pharmacological effects between the 5-6 positional counterparts of the base tryptamines vary widely without much of a pattern. Shulgins data/opiniom is completely outdated in my opinion. Science has progressed leaps and bounds since those trials were conducted, and many substances where only bioassed a handful of times before the publishing of pihkal and tihkal.
Let's not get too caught up in Sasha's opinions.

J Med Chem. 2000 Nov 30;43(24):4701-10.
Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines.
Blair JB show Peaks of - Blair JB , Kurrasch-Orbaugh D show Peaks of - Kurrasch-Orbaugh D , Marona-Lewicka D show Peaks of - Marona-Lewicka D , Cumbay MG show Peaks of - Cumbay MG , Watts VJ show Peaks of - Watts VJ , Barker EL show Peaks of - Barker EL , Nichols DE.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Cited by: 67 times (in Google Scholar)
Abstract
A series of fluorinated analogues of the hallucinogenic tryptamines N,N-diethyltryptamine (DET), 4-hydroxy-N,N-dimethyltryptamine (4-OH-DMT, psilocin), and 5-methoxy-DMT was synthesized to investigate possible explanations for the inactivity of 6-fluoro-DET as a hallucinogen and to determine the effects of fluorination on the molecular recognition and activation of these compounds at serotonin receptor subtypes. The target compounds were evaluated using in vivo behavioral assays for hallucinogen-like and 5-HT(1A) agonist activity and in vitro radioligand competition assays for their affinity at 5-HT(2A), 5-HT(2C), and 5-HT(1A) receptor sites. Functional activity at the 5-HT(2A) receptor was determined for all compounds. In addition, for some compounds functional activity was determined at the 5-HT(1A) receptor. Hallucinogen-like activity, evaluated in the two-lever drug discrimination paradigm using LSD-trained rats, was attenuated or abolished for all of the fluorinated analogues. One of the tryptamines, 4-fluoro-5-methoxy-DMT (6), displayed high 5-HT(1A) agonist activity, with potency greater than that of the 5-HT(1A) agonist 8-OH-DPAT. The ED(50) of 6 in the two-lever drug discrimination paradigm using rats trained to discriminate the 5-HT(1A) agonist LY293284 was 0.17 micromol/kg, and the K(i) at [(3)H]8-OH-DPAT-labeled 5-HT(1A) receptors was 0.23 nM. The results indicate that fluorination of hallucinogenic tryptamines generally has little effect on 5-HT(2A/2C) receptor affinity or intrinsic activity. Affinity at the 5-HT(1A) receptor was reduced, however, in all but one example, and all of the compounds tested were full agonists but with reduced functional potency at this serotonin receptor subtype. The one notable exception was 4-fluoro-5-methoxy-DMT (6), which had markedly enhanced 5-HT(1A) receptor affinity and functional potency. Although it is generally considered that hallucinogenic activity results from 5-HT(2A) receptor activation, the present results suggest a possible role for involvement of the 5-HT(1A) receptor with tryptamines.

It's not only Sasha, but also Dave Nichols.

 

[ebola?]

That is fucking horrifying.

I don't see why. Could you please explain further? I mean, it's promiscuous enough that I wouldn't necessarily expect its effects to be desirable, but horror?

ebola

 

[ebola?]

6-Fluoro-DMT possess affinity for the 5-HT1A (392.6 nM), 5-HT1B (217.7 nM), 5-HT1D (55.4 nM), 5-HT1E (460.8 nM), 5-HT2A (866 nM), 5-HT2B (29.8 nM), 5-HT2C (674.2 nM), 5-HT5A (960.5 nM), 5-HT6 (25.6 nM), 5-HT7 (40.8 nM), D1 (547.3 nM), D2 (610.4 nM), D3 (866.8 nM), D4 (1,454 nM), D5 (6,291 nM), α1A-adrenergic (173.3 nM), α2B-adrenergic (295.5 nM), α2C-adrenergic (148.8 nM), H1 (46.6 nM), H2 (925.4 nM), I1 (898.4 nM), 1 (6,892 nM), and 2 (7,128 nM) receptors, as well as the SERT (144.6 nM).[1] It has low/negligible (> 10,000 nM) affinity for the 5-HT3, α1B-adrenergic, α2A-adrenergic, β1-adrenergic, β2-adrenergic, H3, H4, and M1-M5 receptors, as well as the DAT and NET.[1] It has not been screened at 5-HT1F, 5-HT4, α1D-adrenergic, β3-adrenergic, or VMAT1/VMAT2.

citation? Where are these data from? With access to the full article, we could perhaps yield a more specific idea of these figures' implications. Speculatively:

Well, this one looks markedly similar to 5-meo-mipt, a reasonably well-tolerated compound, only with oddball high affinity for H1. Activity there is not unknown among psychedelics. If it acts as an antagonist...well, it might be a drowsier trip. As an agonist? Maybe more 'alerting' or 'stimulating', but in an as of yet uncharacterized way.

The histamine and adrenal effects scare me as far as psychedelics go.

Prominent adrenal effects are rampantly common for phenethylamine psychedelics.

the pharmacological effects between the 5-6 positional counterparts of the base tryptamines vary widely without much of a pattern.

Have we yet collected sufficient data to claim such?

I have to say i'd imagine it would feel like all the lights are on, and no one is home.
Where ever "you" go.
Lets just hope the hardware is in a good enough piece to accept you back.

Why do you think this?

I wonder if this compound could precipitate seratonin syndrome by itself seeing as its not only a 5HT a-b agonist as well as exibiting SERT, DAT, and NET action?

Most known entactogens share this type of activity profile.

It's just the sheer number. If you take a look at traditional psychedelics, its generally only a few receptor sites.

No, most known psychedelics are pretty broad-spectrum in activity.

LSD's agonism of D2 receptors contributes to its psychoactive effects.

At sensible doses, probably not. Referring to the chart Entheo posted, the line marks the cut off for likely relevance at sensible dosages. Now eat a quarter sheet plus, and we have a different story. Also, LSD's first-order metabolite is more dopaminergic.

I do imagine that you can reach a higher affinity, if wreckless doses were taken....

No, binding affinity measures the relationship between concentration of drug in solution and receptor occupancy. As an analogy, objects do not become more dense just by being really large even if they are heavy.

ebola