Drug info - Bromo-dragonfly

[HippieD9]

Please post info about Bromo-Dragonfly here.
Can anyone add information about:

• names / synonyms
• molecule
• dose
• duration
• side effects
• have there been any reported incidents with this compound?
• since when has this research chemical been available?
• legal status
• stability of the molecule / compound

Experiences with Bromo-Dragonfly should be posted here: Bromo-Dragonfly (Br-DFLY) trip reports
These documents about Bromo-Dragonfly are in the file archive

This compound has caused deaths.

Bromo-DragonFLY
Chemical name
Bromo-benzodifuranyl-isopropylamine or
(1-(8-bromobenzo[1,2-b;4,5-b']difuran-4-yl)-2-aminopropane
Chemical formula
C13H12BrNO2
Molecular mass
294.15 g/mol
Melting point
decomposes at 240 °C (hydrochloride)


CAS number
-
N[C@H](C)CC1=C(OC=C2)C2=C(Br)C3=C1C=CO3 (R-isomer)


Bromo-DragonFLY is a psychedelic hallucinogenic drug of the phenethylamine family. Bromo-DragonFLY is considered an extremely potent hallucinogen, comparable in dosage to LSD, and it has an an extremely long duration of action. Bromo-DragonFLY has a stereocenter and R-(-)-bromo-DragonFLY is the more active stereoisomer.
Pharmacology
The hallucinogenic effect of bromo-DragonFLY is mediated by its partial agonistic activity at the 5-HT2A serotonin receptor, but bromo-DragonFLY also has a high binding affinity for the 5-HT2B and 5-HT2C serotonin receptor.

History
Bromo-DragonFLY was first synthesized by Matthew A. Parker in the laboratory of David E. Nichols in 1998.

Anyone know any more about this? Possibly aka Br-DFLY or difuranyl-DOB

[Alfa]

<H3>
<CENTER><BIG>Dihydrobenzofuran analogues of hallucinogens.
4. Mescaline derivatives</BIG>
by
Monte AP, Waldman SR, Marona-Lewicka D,
Wainscott DB, Nelson DL, Sanders-Bush E, Nichols DE.
Department of Medicinal Chemistry and Molecular Pharmacology,
School of Pharmacy and Pharmacal Sciences,
Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 1997 Sep 12;40(19):2997-3008

ABSTRACT</CENTER></H3>
<BLOCKQUOTE><BIG><BIG>D</BIG></BIG>ihydrobenzofuran and tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in the prototypical hallucinogen, mescaline (1). Thus, 4-(2-aminoethyl)-6,7-dimethoxy-2,3-dihydrobenzofuran hydrochloride (8) and 1-(8-methoxy-2,3,5,6-tetrahydrobenzo[1,2-b:5,4-b']difuran-4-yl)-2- aminoethane hydrochloride (9) were prepared and evaluated along with 1 for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg). Also, 1, 8, and 9 were assayed for their ability to displace [3H]ketanserin from rat cortical homogenate 5-HT2A receptors and [3H]8-OH-DPAT from rat hippocampal homogenate 5-HT1A receptors. In addition, these compounds were evaluated for their ability to compete for agonist and antagonist binding to cells expressing cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Finally, agonist efficacy was assessed by measurement of phosphoinositide hydrolysis in NIH 3T3 cells expressing the rat 5-HT2A or 5-HT2C receptors. Although 1 fully substituted for LSD in the DD assays (ED50 = 33.5 mumol/kg), neither 8 nor 9 substituted for LSD, with just 50% of the rats administered 8 selecting the drug lever, and only 29% of the rats administered 9 selecting the drug lever. All of the test compounds had micromolar affinity for the 5-HT1A and 5-HT2A receptors in rat brain homogenate. Curiously, the rank order of affinities of the compounds at 5-HT2A sites was opposite their order of potency in the behavioral assay. An evaluation for ability to stimulate phosphoinositide turnover as a measure of functional efficacy revealed that all the compounds were of approximately equal efficacy to serotonin in 5-HT2C receptors. At 5-HT2A receptors, however, 8 and 9 were significantly less efficacious, eliciting only 61 and 45%, respectively, of the maximal response. These results are consistent with the proposed mechanism of action for phenethylamine hallucinogens, that such compounds must be full agonists at the 5-HT2A receptor subtype. In contrast to the 2,5-dimethoxy-substituted phenethylamines, where rigidification of the methoxy groups had no deleterious effect on activity, the loss of activity in the 3,4,5-trioxygenated mescaline analogues may suggest that the 3 and 5 methoxy groups must remain conformationally mobile to enable receptor activation. </BLOCKQUOTE>

[Alfa]

More info is to be found here: http://pubs3.acs.org/acs/journals/do..._doi=10.1021/j m9803525


You need to purchase the document(pdf).


Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists.

Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, Nichols DE.

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.

The affinity of ligands for either the 5-HT(2A) or 5-HT(2C) agonist binding site was enhanced by modification of the 2,5-oxygen substituents that are found in typical hallucinogenic amphetamines such as 4b (DOB). Restriction of the conformationally flexible 2,5-dimethoxy substituents into fused dihydrofuran rings generally resulted in increased potency relative to the parent 2,5-dimethoxy compounds. The pure enantiomers of these arylalkylamines were obtained by enantiospecific synthesis that involved acylation of the heterocyclic nucleus 7 with N-trifluoroacetyl-protected D- or L-alanyl chloride, followed by ketone reduction and N-deprotection. The enantiomers demonstrated modest stereoselectivity at the two receptors. Several general trends within these classes of new compounds were observed during their pharmacological investigation. For most pairs of optical isomers tested, the R-enantiomers of the compounds containing heterocycle 7 bound with only slightly higher affinity than their S-antipodes at the 5-HT(2A) and 5-HT(2C) receptors. Likewise, functional studies indicated that the R-enantiomers generally displayed increased potency compared to the S-enantiomers. Aromatization of the dihydrofuran rings of these arylalkylamines further increased affinity and potency. Only a few compounds were full agonists with most of them possessing intrinsic activities in the range of 60-80%. These compounds with a fully aromatic linear tricyclic nucleus are some of the highest-affinity ligands for the 5-HT(2A) receptor reported to date.






Bromo-DragonFLY IUPAC nomenclature, Chemical nameBromo-benzodifuranyl-isopropylamine or(1-(8-bromobenzo[1,2-''b'';4,5-b']difuran-4-yl)-2-aminopropane Chemical formulaC13H12BrNO2 Molecular mass294.15 g/mol Melting pointdecomposes at 240 °C (hydrochloride) CAS registry number, CAS number- Simplified molecular input line entry specification, SMILESN[C@H](C)CC1=C(OC=C2)C2=C(Br)C3=C1C=CO3 (''R''-isomer) Image:R-<B style="COLOR: black; : #ffff66">Bromo-DragonFLY[/B].png, chemical structure of (''R'')-<B style="COLOR: black; : #ffff66">Bromo-DragonFLY [/B]<B style="COLOR: black; : #ffff66">Bromo-DragonFLY[/B] is a psychedelic hallucinogenic drug of the phenethylamine family. <B style="COLOR: black; : #ffff66">Bromo-DragonFLY[/B] is a the most potent known hallucinogen, it is even more potent than LSD but it has an an extremely long duration of action. <B style="COLOR: black; : #ffff66">Bromo-DragonFLY[/B] has a stereocenter and ''R''-(-)-<B style="COLOR: black; : #ffff66">bromo-DragonFLY[/B] is the more active stereoisomer. Pharmacology The hallucinogenic effect of <B style="COLOR: black; : #ffff66">bromo-DragonFLY[/B] is mediated by its partial agonistic activity at the 5-HT2A 5-HT receptor, serotonin receptor, but <B style="COLOR: black; : #ffff66">bromo-DragonFLY[/B] also has a high binding affinity for the 5-HT2B and 5-HT2C serotonin Receptor (biochemistry), receptor. History <B style="COLOR: black; : #ffff66">Bromo-DragonFLY[/B] was first synthesized by Matthew A. Parker in the laboratory of David E. Nichols in 1998. See also * 2,5-dimethoxy-4-bromoamphetamine, DOB * PiHKAL External links References * 'A novel (benzodifuranyl)aminoalkane with extremely potent activity at the 5-HT2A receptor' by M. A. Parker, D. Marona-Lewicka, V. L. Lucaites, D. L. Nelson, and D. E. Nichols in ''J. Med. Chem.'' 41(26): 5148-5149 (1998) [http://dx.doi.org/10.1021/jm9803525 DOI: 10.1021/jm9803525] * 'Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT2A/2C receptor agonists' by J. J. Chambers, D. M. Kurrasch-Orbaugh, M. A. Parker, and D. E. Nichols in ''J. Med. Chem.'' 44(6): 1003-1010 (2001) [http://dx.doi.org/10.1021/jm000491y DOI: 10.1021/jm000491y] Categorization {{Hallucinogenic phenethylamines}} ...

[HippieD9]

So it seems to me that this stuff would blow away anything else out there, at least in terms of strength. Anyone know of any experiance reports? It seems to me that this really needs to be investigated.





Peace,


D.

[Labrat]

I for one hopes this one never ever enters the market.Even more sofor the longer lasting trifluoromethyl analogue. They are just way too potent to be handled by idiots. Regular LSD is very benign as far as toxicity goes. The PEA's and amphetaminesare hits another level of toxicity.

[anj0vis]

Since this is potent enough for blotters, it will surface on the
streets pretty soon. There are more than enough of people that want to
make big bucks and what would be better (I don't think so, but I bet
many do) than sell sheets of "acid".



What comes to toxicity, sure nothing has been tested, but since this
would work in µg doses, there are very good reasons why it would have
very low toxicity (or at least very low ld50). It would be very
unpropable that it would act on other receptors as powerfully as in
5ht2 (which in itself is rather safe in actions). Only real problem,
safety-wise, as I see it is the length of the experience. It might
caught many people by surprise negatively.

[Alfa]

From that commercial point of view you would also want satisfied customers with high return sales and low risk on bad experiences. A strong effect with long duration will likely give exactly the opposite. Duration is exactly what made mushrooms so popular and reduced the popularity of LSD.

[HippieD9]

Not sure about others but I consider duration a positive, longer is better. Then again I don't use these drugs like most people do. I could see a lot of people freaking out on this, I'm sure that if it appears on the streets it'll be scheduled real quick. Unfortunatly it's impossible to keep drugs in the educated RC community. That all being said, I can't wait to get my hands on this if it ever is available.





Peace,


D.

[Triple7]

here is another fly.. which is much less potent.. i know nothing about
chemistry.. but i am just curious why the aromatized rings that make a
dragon makes something much more potent.



http://www.nis.atr.jp/~ray/pubs/Tucson04/2C-B-fly.html



anyone who can pm some 'biochem drug sites for an compleete idiot' who likes ot learn?? you guys are talking too much chinese.

[Nagognog2]

Hmmm... I smell another STP disaster on the horizon. I can just see people taking a hit of this and, expecting LSD-effects in 15 or 20 minutes, doubling and tripling the dose. Get out the margarine ambulance and the BIG bottle of valium.

[fastandbulbous]

but i am just curious why the aromatized rings that make a dragon makes something much more potent.


------------------------------------------------------------ -





It's because the fully aromatic dragonfly molecules are planar, and that allows the best conformation for binding to the 5HT2a receptor. LSD has most of all four ring systems in the same plane because the aromatic pi electrons are conjugated all the way up to the carboxyl group of the amide function (keto-enol tautomerism)

[HippieD9]

Just found this lil tidbit, I can't wait for this book!





From the working draft of an upcoming book by Shulgin, "Psychedelic Index", Transform Press, 2004



<CENTER></CENTER>


Names:


2C-B-FLY
1-(8-Bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminoethane


Registry Numbers:


CARN
HCL salt 178557-21-6


Natural sources:


Not known in nature


Synthesis:


From hydroquinone (with 1-chloro-2-bromoethane) to 1,4-bis(2-chloroethoxy)benzene (with Br2) to 1,2-bis(2-chloroethoxy)-2,5-dibromobenzene (with BuLi) to 2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran (with dichloromethyl methyl ether) to 4-formyl-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran (with CH3NO2) to 4-(2-nitro-1-ethylene)-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran (with LAH) to 1-(2,3,6,7-Tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminoethane (with Br2) to 2C-B-FLY (Monte, et al., 1996).


History:


The "FLY" name was inspired by the two dihydrofuran rings that extend oppositely from the sides of the benzene ring. When they are aromatized (furan rings) they are planar with the benzene ring and the code name is "DRAGONFLY" and they are listed as DFLY derivatives.


Physical properties:


C12 H14 Br N O2
HCl salt m.p. &gt;310 (EtOH, EtOAc) (Monte, et al. 1996).


Pharmacology:


The five "FLY" compounds (2C-FLY, 2C-B-FLY, FLY, B-FLY and DOM-FLY) were assayed in a drug discrimination paradigm with LSD-trained rats, and in interactions with various serotonin receptors. (Monte, et al., 1996).
2C-B-FLY is active in man at an oral dose of 10 milligrams (Shulgin, 2003a)


Legal Status:


2C-B-FLY is not listed in any law.

[anj0vis]

I wonder why DOM-FLY is not called D-FLY or M-FLY, since that would be more logical (like following 2C-D nomenclature or then using the logical M for Methyl). 2C refers to phenethylamine and obviously B-FLY is the amphetamine analogue (should be DOB-FLY if written like DOM-FLY).

[fastandbulbous]

It would definitely make for some of the stranger names, if you start considering the benzodifuran derivatives of the beta-methoxy compounds from PIHKAL.


You end up with BOB-FLY and BOD-FLY (the second one based on the DOM ring substitution pattern sounds like somthing that carries nasty diseases!)

[Nagognog2]

I assume in case of a bad trip on BOD-FLY, one would then reach for the BLACK-FLAG. And if it were to be outlawed, you could expect RAID.

[ChemicallyBound]

From hydroquinone (with 1-chloro-2-bromoethane) to 1,4-bis(2-chloroethoxy)benzene (with Br2) to 1,2-bis(2-chloroethoxy)-2,5-dibromobenzene (with BuLi) to 2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran (with dichloromethyl methyl ether) to 4-formyl-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran (with CH3NO2) to 4-(2-nitro-1-ethylene)-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran (with LAH) to 1-(2,3,6,7-Tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminoethane (with Br2) to 2C-B-FLY (Monte, et al., 1996).


__________________________________________________ _______


Not an absolutely bad synth route at all!


BUT, it is not active apparently in sub 10mg levels in humans as previously thought even though it is the most potent 5HT-2 binding affinity there is.

[fastandbulbous]

BUT, it is not active apparently in sub 10mg levels in humans as previously thought even though it is the most potent 5HT-2 binding affinity there is.


Which, 2C-B-FLY or bromodragonfly? I ask as the bromodragonfly is active in humans at sub milligram levels (I've heard nowt about the human dose of the phenethylamine though)

[anj0vis]

and that 2c-b-fly is the nonaromatized version, aromatized (furan rings) version is much more potent. I don't know how big difference there is, but if it is say (guessing) 5-fold, we would see activity at 2mg+, which is already quite good.

[ChemicallyBound]

Ah, the bi-furan rings are the diff. between 2c-b-fly and b-dragonfly,


missed it at first glance. Haven't had time to look at MA Parkers route yet, I'd assume its not too different. Has this one actually been bioassayed then for definitive activity in human?

[ethacetin]

Hello, I have some questions regarding this compound.



I read an article by David E. Nichols in which he was testing out
conformations of the phenethylamine molecule (the article was exploring
the possible missing link between the tryptamine and phenethylamine
worlds) and more specifically which conformation the ethylamine chain
preferred to be in.



He made a series of test compounds, all resembling these DragonFLYs,
except that he only bound the oxygen at the 5-position in a furan ring
and left the 2-methoxy group as it was.



I'm really sorry that i can no longer find the article, but in light of
the trends Shulgin found in his Tweetios (2-EtO- compounds yield a
shorter duration and a lower potency, 5-EtO- compounds have a
relatively unchanged potency and a longer time duration, and 2,5-DiEtO-
homologues are very weak, if active at all), i was wondering if it
would be better to in fact leave this 2-methoxyl group alone and not
extend it or if attaching both oxygens back to the benzene ring does in
fact yield a more potent, longer lasting, or overall "better"
compound.



If anyone has any information or an opinion about this it would be greatly appreciated.



Thanks

[fastandbulbous]

If it's just the 5-methoxy group that's contained in a furan ring (the 2-methoxy being left as it is), it has more than a passing resemblance to a 5-methoxyindole nucleus. That way, you have a pretty good match to the structure of serotonin - for binding at the 5HT2a receptor.


I wrote a long post at another forum comparing 5HT2a agonists and SAR activity. I hope this isn't against the rules, but I'll post a link to it as I'm not too confident about how to post the whole thing here
[PEdited by: BA

[anj0vis]

I have also wondered sometimes that if alpha-methyl group in DO-X or these FLY compounds would be replaced by amino group, NH2, would it still be almost as active as amphetamine version? Would be interesting to know. If the activity is something between amphetamines and phenethylamines, it would still be quite useful class.

[ChemicallyBound]

<TABLE cellPadding=2 width="100%">
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<TD vAlign=center width="100%" background=http://i1.bluelight.nu/p/10.gif bgColor=#e8e8f1>Acid, dragonflies and the 5HT2A receptor 15-11-2004 01:45</TD>
<TD align=right bgColor=#e8e8f1>(#2448978)</TD></TR></T></TABLE>
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<TD>Factors that influence the structure-activity relationship (SAR) of psychedelic drugs with respect to their agonist activity and binding at the 5HT2A receptor site - a possible new series of high potency 5HT2A agonists

The 5HT2A receptor is possibly the most important when it comes to investigating the actions of psychedelic drugs. These drugs belong almost exclusively to the phenethylamine, tryptamine and ergoline groups of compounds. The other sites that are believed to be important in how they exert their activity are the 5HT1A and 5HT2C receptors (the arrangement of the sites important for binding of compounds to the 5HT2C site are remarkably similar to those of the 5HT2A receptor).

In binding studies using cloned 5HT2A receptor, the drug(s) used in assays using radiolabelled markers are DOB and DOI (4-bromo-2,5-dimethoxyamphetamine and 4-iodo-2,5-dimethoxyamphetamine, respectively). SAR studies carried out by A Shulgin, and documented in the book PIHKAL have shown the following to be needed for maximum activity:

A ring substitution pattern that has methoxy groups at positions 2 and 5 on the benzene ring. Any variation, by either substitution of ethoxy groups for one or both methoxy groups, or substitution into the benzene ring in a pattern other than at position 2 and 5, leads to a reduction of activity; in most cases, this produces a marked fall in activity.

Substitution into the benzene ring at the 4 position with a hydrophobic group. Compounds formed by the use of any of the following groups have shown activity at doses under 100mg in man: alkoxy; alkyl; halogeno or thioalkyl. In order of the potency of the compound formed, they show the following pattern

Most potent… halogeno &gt; alkyl &gt; thioalkyl &gt; alkoxy …least potent.

Within those groups, the more hydrophobic the group, the higher the activity. This is only limited by stearic considerations when the groups become very large. So for each group, the ordering is as follows:

Halogens Iodo &gt; bromo &gt; chloro &gt;&gt; fluoro

Alkyl Propyl &gt; ethyl &gt; methyl &gt;&gt; butyl &gt;&gt; pentyl(amyl)

Thioalkyl Propylthio &gt; ethylthio &gt; methylthio

With the alkoxy substituents, the nature of the intoxication seems to change qualitatively as the group gets bigger.

On the side chain, bearing the ethylamine function, an alpha methyl group (amphetamines) gives greatest activity, followed by the unsubstituted chain (phenethylamines). Substitution into the alpha position by a group larger than methyl abolishes any psychedelic activity.

Alpha substitution activity… methyl &gt; hydrogen &gt;&gt;&gt; ethyl.

Using the above data from PIHKAL, the most potent compound is either DOI or DOB, as both were fully active at about 2.5mg. Fig 1 shows how the relevant substitution pattern interacts with the 5HT2A receptor (diagram modified from original present in a paper by D Nichols)





Further developing the SAR theme started by Shulgin, Nichols produced some conformationally restricted analogues of DOB (they’ve been nicknamed the “dragonfly” compounds, most probably because of their structural resemblance to said winged insects). Fig 2 shows the structure of a couple of the “dragonfly” compounds, and DOB for comparison. Also given are receptor binding data for the three compounds.






As can be seen from the binding data, both of the dragonflies are more active than DOB, the three ringed, fully aromatic compound being the most potent (the dihydrofuran derivative is fully active in man at a dosage of 800-1000ug (0.8-1.0mg), and the fully aromatic furan derivative should be active at an even smaller dosage in man). The lone pairs of electrons on the oxygen atoms of the methoxy groups have been prevented from rotation by incorporation into a furan ring system fused with the benzene ring. The fully aromatic compound shows even more activity, and this is thought to be because all of the atoms of the three rings lie on the same plane. This is thought to be needed for maximum activity (with tryptamines, the indolic nitrogen is in the same space as the oxygen of the 5-methoxy group. Only difference is that nitrogen has only 1 lone pair electrons. The 2-methoxy group corresponds to the 5-hydroxy group of serotonin)

Fig 3 shows how the fully aromatic dragonfly compound would interact with the 5HT2A receptor, and its structure is compared with LSD (the aromatic dragonfly compound’s structure has been overlaid that of LSD for easier comparison. Also, the structure of 5HT/serotonin has also been overlaid that of LSD).





It can be speculated that one of the reasons that LSD shows such high potency as a psychedelic agent in man is because all of the atoms of the indole nucleus, and that of the ring directly attached to it (rings a, b and c – see fig 5), all lie in the same plain, hence presenting a flat face to the receptor. Reduction of the double bond of the other ring (the d ring, that contains the tertiary amine function), abolishes the activity of LSD. Reduction of this bond also removes the conformational restraint that holds the a, b and c ring in the same plane, and the carbon atom at position 4 in LSD is forced either above or below the plane of the indole nucleus. This pushes it into the region of stearic occlusion, which in turn abolishes any activity. It is this area of stearic occlusion that is responsible for the loss of activity when an alpha methyl group is replaced by an alpha ethyl group in the phenethylamine hallucinogens (and why the 2-aminotetralin derivatives are devoid of activity – the saturated ring would not be flat, but would take a modified version of the boat/chair form that cyclohexane exhibits)..

Fig 4 shows a comparison of activity of the 2,5-dimethoxy-4-methylamphetamine (DOM) that occurs with different substitution patterns into the sidechain ethylamine function. As expected, there is a loss of activity that comes with the loss of the alpha-methyl group to give the compound 2C-D. Movement of the methyl group from the alpha position to the beta position causes activity to drop off dramatically (beta-methyl 2C-D). Replacement of the beta-methyl group with a beta-methoxy group (to give BOD), shows a twofold increase in activity over 2C-D. This being the case, the lack of activity of beta-methyl 2C-D cannot be explained as being due to stearic hindrance, as the methoxy group is quite a bit larger than the methyl group. Other than the size of the groups, the other main difference is that the oxygen atom of the methoxy group has two lone pairs of electrons, whereas the methyl group has none.





At this point, it is advantageous to look at the comparison of two tryptamine hallucinogens, in order to shed some light on the activities of the DOM/2C-D derivatives. Comparing N,N-dimethyltryptamine (DMT), with its 4-hydroxy derivative (psilocin), one would expect to see a reduction in activity in psilocin, as the polar OH group would reduce the ability to cross the blood brain barrier: What in fact is seen is a 5 fold increase in activity.





Fig 5 shows the structural configuration of psilocin and BOD superimposed over that of LSD. The thing that they have in common is that the oxygen atom in each compound is in a position to donate lone pairs of electrons into the space that would be occupied by the delocalised pi electrons of the double bond in LSD. The lack of activity of beta-methyl 2C-D confirms that there needs to be negative charge in the area of the double bond. It comes from the delocalised pi electrons in the case of LSD, and lone pairs in the case of psilocin and BOD. Because beta-methyl 2C-D “sticks an atom” into that space, but without a concentration of negative charge to interact with the positive charge in the receptor protein, it binds much more weakly than either 2C-D (doesn’t try to push a methyl group in there) or BOD (oxygen atom puts negative charge – lone pair electrons – into that space) Fig 5a shows distribution of negative charge (pi electrons) around double bond in d ring.





As well as contributing the negative charge, the double bond holds all 4 carbon atoms in the same plane as the atoms of the benzene ring, which as mentioned earlier is very important for receptor binding. The proposed phenethylamine/amphetamine 5HT2A agonists in fig 6 have the whole phenethyl skeleton held in the same plane due to the conjugation of the pi electrons with the delocalised electrons of the benzene ring, as well as presenting the pi electrons in the correct position. They should be more potent than their corresponding amphetamine derivative, as they will bond more strongly to the receptor. This also removes any complications that might occur with any adrenergic receptor interaction (the beta-hydroxy 2C-D derivative, BOHD caused a large drop in blood pressure – in fact the drug methoxamine has the 2,5-dimethoxy configuration, and a beta-hydroxy group, and it is a potent pressor agent), as the beta-hydroxy oxygen atom is in the same position as the benzylic hydroxy group oxygen atom. The corresponding DOM derivative would be 3-amino-2-(2,5-dimethoxy-4-methylphenyl)butene, and the 2C-D derivative would be 3-amino-2-(2,5-dimethoxy-4-methylphenyl)propene.





Also shown in fig 6 is a modification that retains the double bond, substituted into a tryptamine, but retaining the conjugated system of the aromatic nucleus (indole instead of benzene). This would produce a series of 4-vinyl-N, N-dialkyltryptamines, which again should be more potent than their corresponding 4-hydroxy-N,N-dialkyltryptamine, and as the group is far less polar, so should allow better penetration of the blood brain barrier






Fig 6a shows all these modifications taken to their logical conclusion in the double bond version of the fully aromatic dragonfly molecule. If in this molecule, there is an increase in potency of the same magnitude as would be expected when applied to DOB etc, then it could possibly be a phenethylamine derivative that is on a par with LSD in terms of binding, dose etc


Numbering system of phenethylamines, tryptamines and ergolines is outlined in the jpeg attachment



If anybody can be bothered to plough though all of that, please point if I’ve not seen some obvious flaw in my reasoning


Papers referenced

James J. Chambers, Deborah M. Kurrasch-Orbaugh, Matthew A. Parker, and David E. Nichols. Enantiospecific Synthesis and Pharmacological Evaluation of a Series of
Super-Potent, Conformationally Restricted 5-HT2A/2C Receptor Agonists. J. Med. Chem. 2001, 44, 1003-1010

Nicholas M. Barnes; Trevor Sharp. A review of central 5-HT receptors and their function. Neuropharmacology 38 (1999) 1083–1152

David E. Nichols, Ph.D. The Medicinal Chemistry of Phenethylamine Psychedelics. The Heffter Review of Psychedelic Research, Volume 1, 1998

F. A. B. Aldous, B. C. Barrass, K. Brewster, D. A. Buxton, D. M. Green, R. M. Pinder, P. Rich, M. Skeels, and K. J. Tutt. Structure-Activity Relationships in Psychotomimetic Phenylalkylamines. J.Med. Chem., 2974, Vol. 27, No. 20 1100 - 1111

Nichols D.E, LSD and Its Lysergamide Cousins. The Heffter Review of Psychedelic Research, Volume 2, 2001, 80-87

Shulgin Ann & Alexander T. PIHKAL (Phenethyamines I Have Known And Loved)

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The final bit was just theoretical pondering on what should happen, but it’ll really need somebody to synthesize it and carry out trials with it to definitely confirm or deny the activity</TD></TR></T></TABLE>

[DrugPhreak]

Shulgin's way will be easier, but this is one scheme...








2005-03-09_112336_nichols-dragonfly-2.pdf

[ChemicallyBound]

DDQ in rxn g looks like it'll be the toughest part to get