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

[ebola?]

If you have selective DARIs then what is the need for the releasers?

Monoamine releasers feel really different from reuptake inhibitors.

ebola

 

[bluedom]

Is that really a general comment and true for all monoamines? What serotonine releasers are there? I guess MDMA could be classified as one. It is probably more analogous to amphetamines than to cocaine which is somewhat analogous to an SSRI though cocaine's action is rather immediate.

And suppose we could agree they feel different, then would you say that the releases are "better" than MORIs or worse? I'd say cocaine is "better" subjectively than amphetamines, and even better for your health than amphetamines.

I think a separate thread discussing this issue (what EA proposed) would be interesting.

(I'm currently in the process of designing/finding such compounds for the record.)

Monoamine releasers feel really different from reuptake inhibitors.

ebola

 

[bluedom]

But then they're not selective to dopamine (I guess we're using the terms "selective" and "specific" interchangeably), so they won't be a selective/specific DRI if they also act as NDRIs...

There's no guarantee that they'll act as similarly as NDRIs and NDRAs, between which there are already big enough differences that one might want to use one instead of the other
Just speculating, since alpha 1 receptor activation increases basal dopamine release IIRC then maybe selective DRIs have a low ceiling of efficacy which DRAs might not have.

 

[Vader]

Monoamine releasers feel really different from reuptake inhibitors.

I'm not entirely sure I agree, to me mephedrone feels more similar to cocaine than MDPV does.

 

[Enix150]

^Don't meph and MDPV do both? I agree mephedrone is more like cocaine than MDPV, but it's also more like MDPV than cocaine is... It's like a spectrum with meph in the middle? I just wish we could fill in all the blank space. If we determined affinities for some of these RC's, then we could get some real rational design going on.

 

[TheAppleCore]

Quick question...

With regard to theoretical aMT-related neurotoxicity, nuke said:

I'm guessing that the problems are similar to MDMA, in that many of the metabolites of monoamines under high temperature conditions and with high levels of oxidants do to the breakdown of monoamines are going to be excessively toxic.

So, here nuke is referring to endogenous monoamines such as the serotonin, dopamine, and norepinephrine released by aMT. Wouldn't the body metabolize exogenous monoamines like psychedelic tryptamines and phenethylamines in much the same way, resulting in similar or identical toxic metabolites, though? If the metabolites of monoamines are "excessively toxic" under high temperature conditions, then wouldn't something like psilocybin also be neurotoxic, if taken at an outdoor festival on a very hot day, for example?

 

[Epsilon Alpha]

My guess is that a bit dependent on dosage (things like MDMA are easily >100mg), and the fact most hallucinogens don't cause massive monoamine release.
Massive doses of 5HT2A agonists are toxic according to some studies though.

 

[TheAppleCore]

^ Hmm. When you take a reasonable dose of magic mushrooms, I'm guessing you're probably getting something on the order of 20-40 mg active tryptamine alkaloids. If the metabolites of a standard dose of mushrooms are not substantially neurotoxic, but metabolites of endogenous SE, DA, & noradrenaline released by MDMA *are* neurotoxic -- and your theory holds true -- then the quantity of monoamines released by MDMA would have to be on another order of magnitude entirely, above the few dozen milligrams of tryptamine that you ingest when you take mushrooms. Perhaps hundreds of milligrams of SE, DA, and noradrenaline combined.

If we can verify whether or not this assumption is correct, then we could be enlightened...

 

[sekio]

To the best of my knwoledge, the metabolites of serotonin/dopamine/NE/adrenaline are basically non-toxic. The issue is e.g. oxygen and peroxide radicals being generated when monoamine oxidase processes the compound. I personally think this is only an issue where there is an abnormally high concentration of monoamines.

It has been said that having the pair of hydroxyl groups increases toxicity because it can redox cycle to an ortho-quinone and back again. But neither dopamine, norepinephrine, adrenaline, or even alpha-methyldopamine or O-methyldopamine are actually neurotoxic. 2,5-bis-(glutathion-S-yl)-alpha-methyldopamine (a mouthful indeed) was found to be toxic, however, and is a metabolite of alpha-methyldopamine (and also MDMA).

No major metabolites of the monoamine neurotransmitters are toxic in normal concentrations. (substituted phenylacetate/indole-3-acetic acid)

 

[atrollappears]

I personally think this is only an issue where there is an abnormally high concentration of monoamines.

Monoamine-depleted animals still show neurotoxic damage, as long as their temperatures are raised as they would be if they were not monoamine depleted.

 

[sekio]

Oh, interesting. So perhaps it's entirely thermal.

 

[Epsilon Alpha]

Maybe *ques dramatic music* its partly mediated by heat sensitive ion channels!
Someone draft up a decent OP for the NE/DA releasers topic! Pwwwweeeeeaaaase?

 

[ebola?]

I'm not entirely sure I agree [that releasers feel vastly different from reuptake inhibitors], to me mephedrone feels more similar to cocaine than MDPV does.

Well, cocaine and mephedrone have relatively balanced activity at all three monoamines, with a skew toward dopamine and NE, and both have a similarly brief duration of action. MDPV is highly selective for DA and NE, with a skew toward activity at NE, with a much longer duration of action, with a slower rise to peak plasma levels. In short, other similarities between cocaine and mephedrone supersede their distinction as releaser versus reuptake inhibitor. Also, many others find MDPV more similar to coke than mephedrone (I find all 3 pretty different from one another).

Don't meph and MDPV do both?

All effective releasers also act as reuptake inhibitors (as if a transporter is reversed, it cannot take up the endogenous ligand).

If we determined affinities for some of these RC's, then we could get some real rational design going on.

The affinities for coke and MDPV are known, and we have some measures of efficacy for mephedrone (though not ec50s). The thing is, reasoning about SAR for psychoactives is in its infancy, so true 'rational drug design' is presently a dream.

ebola

 

[bluedom]

Do all effective releasers work by reversing the transporter? (In a general biological sense this is not true since you can have release by lysis also but I'm asking about neurons; some drugs do seem to produce some effects by partial lysis/rupture/making holes even in neurons.)

SAR for all drugs is in its infancy (I have high standards). After all, we only have the static structures of 80,550 (as of now) proteins from a universe of proteins and all the conformations they can adopt; let alone how drugs bind to those proteins.

Some people are being clever about this. Check out the 2010 NIH Director's Pioneer Awardees (and in general all of them since 2005). There are few awardees who're exploring neuronal circuits using optogenetics and few doing a lot of structure-based in silico drug discovery.

All effective releasers also act as reuptake inhibitors (as if a transporter is reversed, it cannot take up the endogenous ligand).

The affinities for coke and MDPV are known, and we have some measures of efficacy for mephedrone (though not ec50s). The thing is, reasoning about SAR for psychoactives is in its infancy, so true 'rational drug design' is presently a dream.

ebola

 

[atrollappears]

Oh, interesting. So perhaps it's entirely thermal.

Maybe *ques dramatic music* its partly mediated by heat sensitive ion channels!
Someone draft up a decent OP for the NE/DA releasers topic! Pwwwweeeeeaaaase?

I remember reading that heat inhibits the function of glutathione peroxidase (or some antioxidant enzyme). Don't remember if it was a reliable source though.

 

[pharmakos]

randomly stumbled across this really cool looking drug:

http://en.wikipedia.org/wiki/HZ-2

highly selective kappa opiod agonist

sorta looks like a frog imo

 

[sekio]

Pretty. You should post it in the "symmetrical molecules" thread too

 

[Vader]

If one were trying to form a 2C-X freebase, would using NaOH lead to the possibility of nucleophilic substitution at the 4-position, destroying the compound?
EDIT: Now that I think about it, if one were to dissolve, say, 2C-I HCl in water, the chloride anion would dissociate. Could this then act as a nucleophile, leading to formation of 2C-C? Excuse my poor chemistry, but hey, that's what this thread is for!

 

[sn23]

No such reactions would occur. The donor substituents inactivate the ring for nucleophilic substitution. Plus hydroxide and halogenides aren't reactive enough.

 

[Amu]

Do all effective releasers work by reversing the transporter? (In a general biological sense this is not true since you can have release by lysis also but I'm asking about neurons; some drugs do seem to produce some effects by partial lysis/rupture/making holes even in neurons.).

Dextromethamphetamine can cross the cell membrane (due to lipophilicity) directly in the absence of a transporter and induce release