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The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2

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why would dopamine entering a serotonergic neuron cause damage but entering a dopaminergic neuron not cause it? thinking of that dopamine getting inside 5HT neurons explanation for neurotoxicity of MDMA and MDAI + amphetamine combo
 
The whole DA entering the 5-HT neuron and damaging it was just a never proven hypothesis that Nichols or one of the early MDMA researchers once threw out there. It has since been disproven by mephedrone, which simultaneously releases tons of DA and 5-HT but yet does not cause "MDMA type neurotoxicity."
 
Idk, I think the SERT can transport dopamine into the serotonin terminal http://www.ncbi.nlm.nih.gov/m/pubmed/2413404/ http://www.ncbi.nlm.nih.gov/m/pubmed/8016192/ I also don't know if I would compare mephedrone and MDMA :3 Especially if mephedrone doesn't produce "MDMA type neurotoxicity", though it might be a metabolite specific to MDMA that is getting into the neurons through SERTs and causing damage or could even be MDMA itself.

But Neurotic I could be remembering wrong but I was under the impression it was catecholamines being metabolized by MAO-B that might've damaged the serotonin axons to an extent https://www.erowid.org/references/refs_view.php?ID=974 The damage was attenuated by MAO-B inhibitors and increased by more dopamine, while lack of dopamine through different methods meant less to no serotonin damage. Although I should mention a great portion of the increase in neurotoxicity with more dopamine is probably from increased temperature. But I do wonder what the consequence is of having dopamine inside a serotonin axon if that is indeed a thing. One study said even dopamine itself is toxic to serotonin neurons, hydrogen peroxide aside.
 
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Does methylphenidate/derivatives enter the dopaminergic neuron at all? If it does, what effects does it have? Does anyone have any good studies on the (Q)SAR of DAT,TAAR1 or VMAT2?
 
Can someone knowledgeable on opioid SAR shed some light as to why none of the nitrogens in endogenous opioid peptides are tertiary? I thought a tertiary nitrogen was key for opioid activity.
 
As a matter of fact tertiary amine is not necessary for opioid activity and secondary amines, like normorphine, don't necessarily have lower affinity or efficacy than tertiary amines. This paper has some useful information on normorphine and its analgesic potency and what might affect it. I suppose it's less potent in vivo due to increased hydrophilicity (unlike tertiary amines secondary amines can function as hydrogen bond donors aside from acceptors) which makes it cross the blood-brain barrier less effectively. Norbuprenorphine has a comparable affinity to buprenorphine at MOP receptors but it's a substrate for P-gp which transports it out of the brain (source, source).

BTW, almost all essential aminoacids bear a primary amine so when they're bound via a peptide bond in a peptide, the resulting amide ends up secondary. The only essential aminoacid with a secondary amine is proline.
 
Fair enough, I just think that morphine is a rather lipophilic molecule if you consider it as a whole. (Meth)amphetamine still crosses the BBB effectively. I can't see how one methyl group can increase diffusion across BBB that much. Is lipophilicity the only factor in question? I thought having a tertiary amine had something to do with the binding interactions, maybe I was wrong.
 
Dresden said:
It has since been disproven by mephedrone, which simultaneously releases tons of DA and 5-HT but yet does not cause "MDMA type neurotoxicity."
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yeah, i was wondering about that. if that theory (the one i mentioned) made sense then mephedrone should be brain destroying. i was gonna mention mephedrone but then i gave it a google search and found this article here which claimed it was neurotoxic to both DA and 5-HT neurons. they fed rats with some apparently pretty hardcore mephedrone regimens and found reduced paroxetine and DA uptake binding sites 3 and 7 days afterwards. the numbers did raise from rats examined at day 3 to day 7, which is a different pattern than neurotoxic drugs like pCA and MDMA which cause a more sustained reduction... i guess mephedrone shows it is not simultaneous dopamine and serotonin release which is the villain

Cotcha Yankinov said:
But Neurotic I could be remembering wrong but I was under the impression it was catecholamines being metabolized by MAO-B that might've damaged the serotonin axons to an extent https://www.erowid.org/references/refs_view.php?ID=974 The damage was attenuated by MAO-B inhibitors and increased by more dopamine, while lack of dopamine through different methods meant less to no serotonin damage. Although I should mention a great portion of the increase in neurotoxicity with more dopamine is probably from increased temperature. But I do wonder what the consequence is of having dopamine inside a serotonin axon if that is indeed a thing. One study said even dopamine itself is toxic to serotonin neurons, hydrogen peroxide aside.
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pretty complicated stuff... don't know what to make all of that information hah, but i guess that mephedrone, releasing huge amounts of serotonin, comparable to MDMA, and even higher amounts of dopamine, not causing 'neurotoxicity' in the same fashion as MDMA does pretty much leaves it up to metabolites or some other nuance that MDAI shares, and are 'enhanced' by dopamine release... idk...
 
I think it might indeed be something more compound specific with MDMA.. from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997268/ -- "MDMA is metabolized to catechol metabolites which can undergo oxidation to o-quinones that are highly redox-active molecules and produce free reactive oxygen species or nitrogen species radicals (Capela et al., 2006). It is widely believed that it is these oxidation products which may be responsible for the toxicity exerted by MDMA (Capela et al., 2009; Song et al., 2010; Green et al., 2012a), a view supported by the observation that administration of the free radical trapping agent α-phenyl-N-tert-butyl nitrone attenuated the long-term loss of 5-HT in the rat brain induced by MDMA (Colado and Green, 1995). In contrast to MDMA, catechol and quinone metabolites do not appear to be formed as the result of mephedrone metabolism (Figure 2). This distinction may explain why most studies have failed to observe any similar mephedrone-induced neurotoxicity in rat brain. No active metabolites of mephedrone have yet been identified."

I think temperature is incredibly important too, mephedrone seems to cause more hypothermia interestingly. But the only other thing I could think of is an 5-HT2B interaction, seeing as its involved with the SERTs and MDMA and MDMA's toxicity does seem to be associated with SERTs carrying some molecule into the serotonin terminal, and maybe not other amphetamines have as much interaction with 5-HT2B?? Idk though I know 5-HT2B is supposed to be important for substituted amphetamines it sounds like.. Whenever I think 5-HT2B I just think heart valvular disease and not brain serotonin lol, wish I knew more about what it did in the brain.
 
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Would these catechol and quinone metabolites be expected from Methylone metabolism as well?
 
Very likely yes, although less so than MDMA because the beta ketone is prone to metabolism as well.
 
Interesting that UK law leaves 1-(2H-1,3-benzodioxol-5-yl)-3-fluoro-N-methylpropan-2-amine legal due to this f**kup in classifying amphetamines:

(c) any compound (not being methoxyphenamine or a compound for the time being specified in sub-paragraph (a) above) structurally derived from phenethylamine an N-alkylphenethylamine, a methylphenethylamine, an N-alkyl-α-methylphenethylamine, an ethylphenethylamine, or an N-alkyl-α-ethylphenethylamine by substitution in the ring to any extent with alkyl, alkoxy, alkylenedioxy or halide substituents, whether or not further substituted in the ring by one or more other univalent substituents.

I mean - HOLES man!
 
Does it? I think it's covered, as a "N-alkyl-a-methylphenethylamine" substituted with an alkylenedioxy and halide substituent.

"to any extent with ... or" is inclusive, not exclusive, language. Doesn't mean you can avoid it by having BOTH an alkylenedioxy and halide sub.

Besides, the UK lawyers have no sense of humor anyway. I would not be suprised if they "mistakenly" "swapped" the GC traces for one of methamphetamine during the customs inspection...

(Or, wait, shit, you're talking about a halide on the alpha-carbon, not the ring! Sneaky! You trickster!)
 
In the US, at least, there is no parenteral formulation available of amphetamine, d-amphetamine, methamphetamine, methylphenidate, dexmethylphenidate....nada.

The last injectable amphetamine product legally manufactured was Methedrine HCl. Injection, 5mg./ml. 2ml. ampoules, made by Burroughs-Wellcome, (now part of GSK). The FDA recalled 'em all on Jan. 1, 1970.
 
Mephedrone has since been shown to be metabolized by N-dealkylation to the primary amine, by reduction of the keto group to an alcohol, and by oxidation of the aromatic methyl to a aromatic methanol then to an aldehyde and finally to the carboxylic acid. Indeed, no catechols or quinones form or would be expected to form.
 
After a fairly quick search, I didn't find any suggestions that grapefruit inhibits CYP2D6, only 3A4. So according to my understanding, 3A4 is responsible for N-dealkylation of codeine producing the inactive norcodeine while 2D6 is responsible for 3-dealkylation producing morphine. This should mean that if 3A4 is inhibited, more codeine will follow the 3-dealkylation path resulting in more morphine, thus increased opioid effect. My question is, why do people suggest against using grapefruit to potentiate codeine and why do some people say that in their experience grapefruit actually decreases the effects of codeine?
 
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belligerent drunk said:
After a fairly short search, I didn't find any suggestions that grapefruit inhibits CYP2D6, only 3A4. So according to my understanding, 3A4 is responsible for N-dealkylation of codeine producing the inactive norcodeine while 2D6 is responsible for 3-dealkylation producing morphine. This should mean that if 3A4 is inhibited, more codeine will follow the 3-dealkylation path resulting in more morphine, thus increased opioid effect. My question is, why do people suggest against using grapefruit to potentiate codeine and why do some people say that in their experience grapefruit actually decreases the effects of codeine?
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I can't give an answer, but you definitely have the enzymes right. The mechanism you describe would be the same as the one causing Tramadol to be potentiated through grapefruit juice. 3A4 metabolizes to N-Desmethyltramadol, 2D6 to O-Desmethyltramadol, resulting in higher plasma levels of the latter which is a much stronger mu opioid receptor agonist.
 
Can anyone with a good chemistry knowledge explain the mechanism by which an aliphatic carbon chain is hydroxylated? Also, if someone could explain the enzymatic reaction mechanism by which phenethylamine is metabolised into phenylacetic acid, that would be very much appreciated.
 
Is there any way to separate the relative importances of logP and target (receptor, enzyme etc) binding interactions. Both obviously effect how efficacious the drug is. Someone here said a while ago that MDMA injected directly into the brain requires x140 less of a normal dose (in rats at least). I think seeing how big of a role each of these 2 important properties play could be very useful in understanding the mode of action of the drug. Furthermore, wouldn't it be in the better interest of a molecule to actually have a (relatively low) lipophilicity and a high affinity and selectivity for its target. If the opposite were the case, as in the drug was very lipophilic and got into the brain in large amounts, surely there is more of a chance it interacts with undesirable targets causing side effects etc.
 
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