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Neurochemical profiles of some novel psychoactive substances (Eur. J. Pharmacol. )

Check the PLoS one study - psychedelics and the human receptorome? I would wager MDMA's affinity is very high.
 
Uhm is a receptorome a neologism for pharmacophore?

edit: thanks for the answers!
 
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The study in question. Table S2 is the "goodies" - a big excel file full of Ki data.

5ht2b: 4.00 DOB, 4.00 MDA, 4.00 Aleph-2, 4.00 2C-B-fly, 4.00 2C-B, 4.00 TMA, 4.00 psilocin, 4.00 TMA-2, 4.00 2C-E, 4.00 2C-T-2, 4.00 4C-T-2, 4.00 MEM, 4.00 DOM, 3.97 mescaline, 3.93 6-F-DMT, 3.91 5-MeO-DIPT, 3.91 DMT, 3.88 DPT, 3.70 DOET, 3.64 MDMA, 3.48 DIPT, 3.32 5-MeO-MIPT, 3.13 DOI, 3.11 LSD, 3.01 lisuride, 2.72 cis-2a, 2.17 SS-2c, 1.81 RR-2b, 0.69 5-MeO-DMT; 0.00 salvinorin A;
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(side note: MDMA actually has almost nonexistient affinity for SERT! . Wierrrd)

I was under the impression 'receptorome' is a word for the set of all the chemoreceptors that are associated with a species.

Wiki said:
In analogy with the genome, where the genome is the total set of genes, the receptorome can be considered the total set of genes giving rise to receptors or receptor molecules. It could also be seen as the total number of receptor proteins in a certain organism.

The human receptorome constitutes at least 5% of the human genome. It encodes receptors that mediate the physiological, pathological and therapeutic responses to both exogenous and endogenous ligands.
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http://en.wikipedia.org/wiki/Receptorome
 
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Solipsis said:
Uhm is a receptorome a neologism for pharmacophore?
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Not really. The recepterome of an organism is the entire set of unique receptors in that organism. Pharmacophore are the functional groups of a chemical required for binding to a given receptor.
 
Can anyone clarify - in the paper, table 2 presents data for the functional assays as opposed to the binding assays yes?


There was a weak correlation between the Ki values from functional assays (i.e., inhibition of substrate uptake) and from binding assays (i.e., inhibition of radioligand binding) for the transporter proteins, although six compounds had submicromolar Ki values for at least one or other transporter radioligand binding sites (Table 2). Notably high affinities ( <100 nM) were found for methylenedioxybenzedrone- and 5-APB at DAT, naphyrone and 1-naphyrone at SERT, and naphyrone at NET. The poor correlation probably reflects the fact that transporter inhibitors are likely to bind to different sites on the transporter than the radioligands used for displacement assays, and the fact that transporter substrate uptake assays were not performed at equilibrium. These results also suggest that functional measurement of drug effects on substrate reuptake may be the most reliable method of assessing drug effects on monoamine transporters.
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[edit]
Table 2. Effects of novel psychoactive compounds on serotonin (SERT), dopamine (DAT) and norepinephrine (NET) transporter activity. Data represent mean pKi±S.E.M (N=3) and Ki in nM for inhibitory potencies of various novel psychoactive compounds with comparator data for psychostimulants and antidepressants
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I think they're functional assays. but luckily functional assays for monoamine transport inhibition usually line up really well. monoamine release on the other hand...
 
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Transform said:
Does anyone know the 5HT-2B affinity of MDMA?
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The figure in the Ray paper Sekio mentions is given as 500 nm.

You might also want to look at this paper:

Setola et al 2003 "3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) Induces Fenfluramine-Like Proliferative Actions on Human Cardiac Valvular Interstitial Cells in Vitro"
Recent findings have implicated the 5-hydroxytryptamine 2B (5-HT2B) serotonin receptor in mediating the heart valve fibroplasia [valvular heart disease (VHD)] and primary pulmonary hypertension observed in patients taking the now-banned appetite suppressant fenfluramine (Pondimin, Redux). Via large-scale, random screening of a portion of the receptorome, we have discovered that the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) and its N-demethylated metabolite 3,4-methylenedioxyamphetamine (MDA) each preferentially bind to and activate human recombinant 5-HT2B receptors. We also demonstrate that MDMA and MDA, like fenfluramine and its N-deethylated metabolite norfenfluramine, elicit prolonged mitogenic responses in human valvular interstitial cells via activation of 5-HT2B receptors. We also report that pergolide and dihydroergotamine, two drugs recently demonstrated to induce VHD in humans, potently activate 5-HT2B receptors, thus validating this assay system for its ability to predict medications that might induce VHD. Our discovery that MDMA and a major metabolite, MDA, induce prolonged mitogenic responses in vitro similar to those induced by fenfluramine and norfenfluramine in vivo (i.e., valvular interstitial cell fibroplasia) predict that long-term MDMA use could lead to the development of fenfluramine-like VHD. Because of the widespread abuse of MDMA, these findings have major public health implications. These findings also underscore the necessity of screening current and future drugs at h5-HT2B receptors for agonist actions before their use in humans.
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http://molpharm.aspetjournals.org/content/63/6/1223.full

For general queries on binding data, the PDSP database is really useful - http://pdsp.med.unc.edu/pdsp.php
 
sekio said:
[edit]


I think they're functional assays. but luckily functional assays for monoamine transport inhibition usually line up really well. monoamine release on the other hand...
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Yeah quite... this says nothing about the release, really. If these drugs are essentially substrates for the transport proteins, and then producing their effects by messing with VMAT inside the cells, then we should be looking at those interactions to explain mechanisms of effects?

Since we're seeing pretty low values for affinity for SERT and functional assays for MDMA and mephedrone, but in vivo we know they produce massive intracellular increases in serotonin (and dopamine for mephedrone).

Still, this is useful as those 5Ht-2b affinities are very low indeed for 5- and 6-APB, compared to MDMA and fenfluramine. That's a little worrying - but how do we translate the cardiotoxic effects of fenfluramine taken on a daily basis for months to higher affinity drugs that might be taken only once a month, or once a week?
 
I think the consensus is that if you only take single acuute doses, and space them well apart, it's of no real consequence. It's everyday usage (i.e. Phen Fen as an appetite supressant daily) that gets your cardiac tissue fucked.

Since we're seeing pretty low values for affinity for SERT and functional assays for MDMA and mephedrone, but in vivo we know they produce massive intracellular increases in serotonin (and dopamine for mephedrone).
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this can be explained by releasers binding to a different site than the monoamine pocket (place that transport inhibitors bind). I think that's the explanation for MDxx based release of serotonin.
 
sekio said:
I think the consensus is that if you only take single acuute doses, and space them well apart, it's of no real consequence. It's everyday usage (i.e. Phen Fen as an appetite supressant daily) that gets your cardiac tissue fucked.
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IIRC in Les Iversen's book on amphetamines he thought that the danger of taking fenfluramine, in terms of heart valve damage, were pretty massively overstated anyway.

this can be explained by releasers binding to a different site than the monoamine pocket (place that transport inhibitors bind). I think that's the explanation for MDxx based release of serotonin.
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Hmmm yes I suppose... I was just going off Nuke & vektors speculations over on the MDMA-does-not-bind-SERT thread - http://www.bluelight.ru/vb/threads/...tive-substances-(Eur-J-Pharmacol-)?p=11191040

EDIT - Scuse my ignorance but is the monoamine pocket the place where the substrate is picked up to be passed back into the cell? I'm slightly confused because over in that other thread PA talks about different sites for ligands and uptake inhibitors that are not the substrate site...
 
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is the monoamine pocket the place where the substrate is picked up to be passed back into the cell
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I believe so.

Also, I know there have been cases of valvulopathy associated with (methyl)aminorex use before.
 
sekio said:
Check the PLoS one study - psychedelics and the human receptorome? I would wager MDMA's affinity is very high.
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Wasn't it suggested in another thread that this study was significantly flawed and had misleading results? My mistake if not.
 
thanks a lot for that Sekio!!

forgive my ignorance but something I don't quite understand is, if MDMA affinity for 5ht2b is around 500nm plus another 100nm of MDA
and 5/6apb are "only" 14nm and 3nm

why does the paper words it as being so potent and having such a high affinity?

"Some notable high affinity interactions were observed
between 5-HT2B receptors for5-APB(Ki¼14 nM)and6-APB
(Ki¼3.7 nM),and 5-iodo-aminoindane(Ki¼70 nM). Functional
assays of 5-APB and 6-APB confirmed that these compounds
acted as potent(i.e.,nanomolar EC50 values) full agonists at
5-HT2B receptors"

also 6-APB has a "high" affinity on for a2C adrenoceptors, wouldn't this also be an increase cardiovascular risk?
 
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shocked said:
thanks a lot for that Sekio!!

forgive my ignorance but something I don't quite understand is, if MDMA affinity for 5ht2b is around 500nm plus another 100nm of MDA
and 5/6apb are "only" 14nm and 3nm

why does the paper words it as being so potent and having such a high affinity?

"Some notable high affinity interactions were observed
between 5-HT2B receptors for5-APB(Ki¼14 nM)and6-APB
(Ki¼3.7 nM),and 5-iodo-aminoindane(Ki¼70 nM). Functional
assays of 5-APB and 6-APB confirmed that these compounds
acted as potent(i.e.,nanomolar EC50 values) full agonists at
5-HT2B receptors"

also 6-APB has a "high" affinity on for a2C adrenoceptors, wouldn't this also be an increase cardiovascular risk?
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I'm not sure I understand your question... are you asking why the numerical values given for 5-APB are "low" yet their affinity is discussed as "high"? Those numbers are the Ki values, the the lower the numerical value, the higher a drug's affinity for the receptor is.
 
I know that it isn't an ADD question but I've difficulties to understand what a Ki value can tell exactly about a drug action and how to understand/interpret this. Can you explain it to me or post some links where I can find more information about this?

Edit: I tried to post the study complete but didn't manage to do that. Anyways you can find it in the 28 post in this topic! http://www.psychonaut.com/psychedeliques-synthetiques/45411-letude-de-la-semaine.html
 
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Ki is a measure of how tightly a drug moledule 'fits' in the receptor. Nothing more, nothing less.

In some cases though, a better 'fit' is more drug activity.
 
anyone else worried about the very low Ki for the APBs coupled with full agonist activity on 5-HT2B receptors? it in a whole other leage than mdma with those 500nm and partial agonist activity (only about 1/3 the response of 5-HT). i have looked if there's anything comparable out there and the only thing i've found was ergotamine with a Ki in the same range, but it isn't as a full an agonist as the APBs and the prescribed dose is only 1mg.

my 6-APB will surely stay in the freezer until i have further information.
 
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