Super-potent N-benzyl Phens?

Dr.Heckyll

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Just wanted to mention that the paper is available online for free.

This reminds me of a Glennon paper which showed that N-(4-bromobenzyl)-5-methoxytryptamine is a high affinity (sub-nM) ligand for the 5-HT2A receptor. I actually made this one, and it was inactive. Later some paper showed that it's an antagonist.

In this case of course we have some evidence that these compounds are agonists, with 25I-NBOH being slightly more potent than LSD. What disturbs me a bit is that this compound has equal affinity for the DOI and ketanserine binding sites. This was previously thought to be an indication of antagonist activity.

I wish they would have asked the rats what they think about these compounds.

Also an interesting question is if N-(2-hydroxybenzyl)-5-methoxytryptamine would be an agonist.
 

vecktor

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Smyth said:
good find! How long before RC suppliers start banging this one out ;) It certainly looks more profitable than dragonfly.
good stuff

Other work on these was done a couple of years ago in Germany as part of a PhD thesis, the thesis also investigated the n-(2-hydroxy benzyl) and methoxy derivatives of the benzodifuranyl amino ethanes and propanes.then there was a debate then as to whether they were in fact agonists.
If nichols is saying that the N-benzyl dimethoxy phenethylamines are agonists, then great. plus they are much more selective 5ht2c doesn't appear much fun.

Certainly with the tryptamines the N-(2-methoxy benzyl) derivative of NMT was touted as being a super potent agonist and was even sold by a major comapny as such. In fact it turns out to be an antagonist.

don't know how that fuck up occurred. perhaps nichols has made the same mistake

V
 

EN21

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4-Bromobenzyl-5-MeO-T

I am a little bit prejudiced with the N-benzyl-compounds. I remember a paper from Glennon et al. :

Influence of Amine Substituents on 5-HT2A versus 5-HT2C Binding of Phenylalkyl- and Indolylalkylamines. Glennon, Richard A.; Dukat, Malgorzata; El-Bermawy, Mohamed; Law, Ho; De Los Angeles, Joseph; Teitler, Milt; King, Allison; Herrick-Davis, Katharine. Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA. Journal of Medicinal Chemistry (1994), 37(13), 1929-35.

Abstract

The effect of different amine substituents on 5-HT2A and 5-HT2C serotonin receptor binding was investigated for two series of phenylalkylamine and indolylalkylamine derivs. I and II [R = H, R1 Me, Et, (CH2)3Ph, (CH2)4Ph, CH2C6H4R2, R2 = H, F, Cl, Br, iodo, Me, NH2, NO2, OMe; R = R1 = Me; NRR1 = piperidino]. In general, amine substitution decreases receptor affinity;however, N-(4-bromobenzyl) substitution results in compds. that bind at 5-HT2A receptors with high affinity (Ki < 1 nM) and with >100-fold selectivity. Although parallel structural modifications in the two series result in parallel shifts in 5-HT2C binding, these same modifications alter 5-HT2A binding in a less consistent manner.


His most promising compound seemed to be the N-(4-bromobenzyl).5-MeO-T.
I know honorable people who made it and tested it up to 3 mg orally with no effect. The binding data would indicate that this compound should be active at this level. –So the oral availibility might be responsible for that. –Or any other thing.
 

vecktor

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Non hallucinogenic agonists

In all of his recent papers nichols is suggesting that there is the possibility that 5-ht2a agonists can act in two different ways. one is through the PLC system causing turnover of inositol phosphate IP.

Nichols goes on to suggest that the activation of the other downstream signalling system which uses arachidoic acid AA and similar eicosanoids is in fact more closely correlated with hallucinogenic action. However nowhere in the paper can I find any reference to the AA pathway.
the N-(2-hydroxy-benzyl) compounds here activate PLC

the underlying subtext to this is that Nichols believes that he can separate the hallucinogenic action from 5ht2a agonism and that big pharma should fund further research, into non hallucinogenic 5ht2a agonists. I very much doubt that the required functional selectivity could ever be achieved, the patients would simply take more and more until they tripped.

has anyone got any data regarding LSD at 5ht2a and whether it favours AA over IP? perhaps that would clear up the inconsistancy between the extreme potency of LSD versus its receptor affinity and profile.
 

nuke

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^^ three different ways actually, through g-protein coupling, but we have no data on the third (PLD) so we don't know.. nichols muses that that might be why lsd is so potent.

the aa pathway is through pla.

AA release and IP accumulation for various compounds:

(Nichols Hallucinogens Review 2004)
 

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Dr.Heckyll

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Lisuride is a similar case, thought to be a 5-HT2A agonist, but non-hallucinogenic. The above table explains that, though, by lisuride having low intrinsic activity.

An interesting detail of the SAR is that the alpha-methyl derivative (DOI-NBOMe) is the least potent.

Well, these compounds are very easy to make if one has the corresponding phenethylamine at hand, and I'm sure someone will be curious and adventerous enough to try it out. Wouldn't be surprised if that someone is me ;).
 

vecktor

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Dr.Heckyll said:
Lisuride is a similar case, thought to be a 5-HT2A agonist, but non-hallucinogenic. The above table explains that, though, by lisuride having low intrinsic activity.

An interesting detail of the SAR is that the alpha-methyl derivative (DOI-NBOMe) is the least potent.

Well, these compounds are very easy to make if one has the corresponding phenethylamine at hand, and I'm sure someone will be curious and adventerous enough to try it out. Wouldn't be surprised if that someone is me ;).
A rumour says that Alcon Switzerland have studied these and similar compounds as anti glaucoma agents.
 

Dr.Heckyll

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There's also a patent on DOI-derived imidazol(in)es as 5-HT2A agonists and anti-glucoma agents.
 

Dondante

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Vecktor said:
Nichols goes on to suggest that the activation of the other downstream signalling system which uses arachidoic acid AA and similar eicosanoids is in fact more closely correlated with hallucinogenic action. However nowhere in the paper can I find any reference to the AA pathway.
the N-(2-hydroxy-benzyl) compounds here activate PLC
I noticed that too. Although according to Nichols' big review article, Hallucinogens, "... psychoactive vs. nonpsychoactive agonists did not differ in their ability to activate selectively 5-HT2A receptor-mediated PLA2 or PLC signaling."

Here's another recent paper by Nichols. I still need to read it, but it looks like it has some pertinent information with regards to the signaling cascade following 5HT2A receptor activation. I didn't realize that endocannibinoids were in the picture, but apparently they might be. Check out the signaling cascade in the word doc below. It looks like PLC may have some modulatory action on AA production. They don't mention the standard PLA2 as a mechanism for AA production though.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17010161&query_hl=2&itool=pubmed_docsum

Serotonin 5-HT receptor activation induces 2-arachidonoylglycerol release through a phospholipase c-dependent mechanism. Parrish JC, Nichols DE.
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana, USA.

To date, several studies have demonstrated that phospholipase C-coupled receptors stimulate the production of endocannabinoids, particularly 2-arachidonoylglycerol. There is now evidence that endocannabinoids are involved in phospholipase C-coupled serotonin 5-HT(2A) receptor-mediated behavioral effects in both rats and mice. The main objective of this study was to determine whether activation of the 5-HT(2A) receptor leads to the production and release of the endocannabinoid 2-arachidonoylglycerol. NIH3T3 cells stably expressing the rat 5-HT(2A) receptor were first incubated with [(3)H]-arachidonic acid for 24 h. Following stimulation with 10 mum serotonin, lipids were extracted from the assay medium, separated by thin layer chromatography, and analyzed by liquid scintillation counting. Our results indicate that 5-HT(2A) receptor activation stimulates the formation and release of 2-arachidonoylglycerol. The 5-HT(2A) receptor-dependent release of 2-arachidonoylglycerol was partially dependent on phosphatidylinositol-specific phospholipase C activation. Diacylglycerol produced downstream of 5-HT(2A) receptor-mediated phospholipase D or phosphatidylcholine-specific phospholipase C activation did not appear to contribute to 2-arachidonoylglycerol formation in NIH3T3-5HT(2A) cells. In conclusion, our results support a functional model where neuromodulatory neurotransmitters such as serotonin may act as regulators of endocannabinoid tone at excitatory synapses through the activation of phospholipase C-coupled G-protein coupled receptors.

PMID: 17010161 [PubMed - as supplied by publisher]
 
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nuke

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pla is responsible for aa production...plc mediates ip
 

Dondante

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Right, except IP can also cause release of AA through DAG and 2-AG. And 2-AG can be converted to AA through FAAH (fatty acid amide hydrolase) and MGL (monoglycerol lipase). Here's another reference. It's all so confusing!

Role of phospholipase C and diacylglyceride lipase pathway in arachidonic acid release and acetylcholine-induced vascular relaxation in rabbit aorta. Tang X, Edwards EM, Holmes BB, Falck JR, Campbell WB. Dept. of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.

AA is released from phosphatidylcholine (PC) and phosphatidylethanolamine (PE) by phospholipase A2 (PLA2), or from phosphatidylinositol (PI) by phospholipase C (PLC) pathway. The diacylglycerol (DAG) lipase can convert DAG into 2-arachidonoylglycerol from which free AA can be released by monoacylglycerol (MAG) lipase or fatty acid amidohydrolase (FAAH).

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16024567&dopt=Abstract
 
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Dondante

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Vecktor said:
has anyone got any data regarding LSD at 5ht2a and whether it favours AA over IP? perhaps that would clear up the inconsistancy between the extreme potency of LSD versus its receptor affinity and profile.
I know I've murdered this thread, but I stumbled on something that might be interesting with respect to LSD's potency (also from Nichols' most recent paper).
 
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Dr.Heckyll

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It seems to me that the hallucinogenic effects of 5-HT2A agonists is caused by a modulation of NMDA receptors, see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed.

How this modulation is achieved is the question now, but I doubt AA or 2-AE plays any major rolle in it.

A quite interesting detail from this study is that different 5-HT2A agonists (DOB, LSD) cause different wave shapes of the NMDA currents. This might explain why different 5-HT2A agonists have different psychopharmacological effects
 

Helios.

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If what Nichols is wildly claiming is true, then why does
N,N-benzyl,methyl-amphetamine, an old anorexic prescription drug still on the market last I checked, basically s*ck? where * = u.

100x to 300x more potent? Oh come come now.
The Sprague-Dawley rats don't lie, but they don't speak either.
Feel free to prove me wrong through synthesis and human bioassay.
 

MattPsy

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Because of wildly different methods of action?
Agonist behavior vs. monoamine release...
 

Helios.

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Like I said, prove it. It won't pan out. Read between Dr.Heckyll's lines. I used to email Nichols back and forth all the time, and he's not all that at drug design--though his group is quite adept at drug synth.
 

bigmac74

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MattPsy said:
Because of wildly different methods of action?
Agonist behavior vs. monoamine release...
Helios. said:
Like I said, prove it. It won't pan out.
A monoamine will be an agonist at all it's receptors (e.g. serotonin at 5-HT1/2/etc.) where as an agonist will be selective (e.g. 2C-B at 5-HT2a).

P.S: I know 2C-B isn't completely selective towards 5-HT2a, but that's the major part of it's mechanism.
 
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