Neuropharmacology of exotic stimulants

[ebola?]

Lately, I've been hearing about an increased variety of stimulants, ones that I'll never likely taste. I am wondering what we know about their receptor affinities, data on binding strength at particular sites, strength of monoamine release, reuptake inhibition, etc. As useful reference points, we could compare to d-amp, d-meth, cocaine or ritalin, and MDMA.

4-methyl-aminorex: yes, an oldie. Some people say that it's "smoother" and more "introverted" than other stimulants. Others say that it is mildly MDMA-like.

MDPV: IIRC, this is a dopamine reuptake inhibitor with a comparatively low effect on nor-epi'. Then why do many people find it jittery?

desoxy pripradrol: someone in the trip reports thread said that this chemical has a comparatively high propensity to block nor-epi' reuptake. Then why do most people find that it feels so "smooth"?

fencafamine (sp??): again, people find this one smooth. Why? F and B suggests that it is due to mild agonism at mu opioid receptors. Any other reasons?

4-methyl-methcathinone (methedrone): many find this one MDMA-like, but with more of a "fiend factor". Why might this be?

4-floro-methcathinone (flephedrone (lawl)), ethylcathinone, bk-MBDB(ethylone), etc.: similar questions.

methcathinone: many say that this induces a pleasant stimulation, but without increased focus. Why?

ebola

 

[ebola?]

*bump*

Hah...yet another one with no bites.
Perhaps off to ADD?

ebola

 

[Mr Blonde]

I'll shoot it off there for you then.

Don't ever say I don't deliver great customer service. Three minutes after you request and it's done.

 

[nuke]

>>MDPV: IIRC, this is a dopamine reuptake inhibitor with a comparatively low effect on nor-epi'. Then why do many people find it jittery?

Until someone posts actual data for this compound and its affinities, I'm very skeptical about whether or not this is true. I recall seeing somewhere that it was about 1:3 DA:NE, but I can't figure out where that was so those are pretty useless numbers. Desoxypipradrol is supposed to have a much better DA:NE ratio (where DA affinity is preferential).

 

[grue]

We need to look at blood-brain-barrier mechanisms, which are mysterious, perhaps even more than the relative ratios of catecholamine stimulation.

For many, I would even say most people, dextroamphetamine (something like 5:1 NE: DA) is less peripherally stimulating, with fewer adrenergic side effects than mixed-isomer methylphenidate, which most studies report is very preferential for dopamine.

Dose-dependent of course ...

 

[Jamshyd]

Hmm, I was under the impression that jitters were more due to peripheral drug action, rather than central NE action?

In any case, keep in mind that DA eventually breaks down to epinephrine.

 

[5-HT2]

^^^Yes Jamshyd, physical jitters are thought to be due to peripheral effects on catecholamines, primarily on NE.

Also, DA is not broken down to epinephrine in the body. Rather, it is catabolised by MAO to DOPAC (dihydroxyphenylacetic acid), and/or by COMT to 3-methoxytyramine (3-MT), both of which are then further broken down to homovanillic acid (HVA).

 

[Jamshyd]

Oh it isn't?? I could have sworn I read that somewhere in a textbook (I'll try to find the ref.), but maybe they were talking about decay outside the body?

 

[nuke]

Also, DA is not broken down to epinephrine in the body. Rather, it is catabolised by MAO to DOPAC (dihydroxyphenylacetic acid), and/or by COMT to 3-methoxytyramine (3-MT), both of which are then further broken down to homovanillic acid (HVA).

I think he was referring to the conversion via dopamine beta hydroxylase (DA + ascorbate -> NE). It's also membrane bound, so it works within storage vesicles to convert DA to NE.

 

[grue]

Also, DA is not broken down to epinephrine in the body. Rather, it is catabolised by MAO to DOPAC (dihydroxyphenylacetic acid), and/or by COMT to 3-methoxytyramine (3-MT), both of which are then further broken down to homovanillic acid (HVA).

dopamine beta hydroxylase
DA ---> NE

 

[Reminisant B]

Looking at the structure of MDPV, wouldn't be surprised if beta-hydroxy PEA's result from certain metabolic pathways. [?]

[I.e even if MDPV is shown to mostly elicit DA re-uptake, possibly it's metabolites are causing the jitters & peripheral side effects - something that is much harder to predict seeing as it's metabolites have not been researched ?]

 

[ebola?]

Thanks all. This has been very informative. RE peripheral effects: do jittery stimulants tend to directly agonize somatic adrenal receptors or cause release/block reuptake a la their effect on monoamines in the brain?

ebola

 

[IlostaMadge]

In my experience mephedrone/4 methyl methcathinone is not like MDMA at all.
It seems to cause dopamine release upon consumption unlike MDMA that promotes DA release via other mechanisms and has a far longer come up.
The DA release from 4MMCAT seems to cause fiending in it's users.

BK-MBDB fascinates me, it is more potent than MBDB (which goes against the BK trend) and seems to be a stimulating, primarily DA compound whereas MBDB is reported as totally different.

 

[MattPsy]

[oops, double post, remove plz]

 

[MattPsy]

bk-MBDB made my heart pound like nothing else, kinda scary actually. Nothing like peaking your nut off, experiencing "bum wee" (which it is also infamous for), thinking you're gonna have a heart attack...

My suggestions for things we should be looking at for stimulants:

- Compound distribution in the body. Where does it go, mostly? We would prefer it go to the CNS, so as to minimize peripheral effects.
- DA:NESE?) ratio. Doesn't matter how this is achieved by whatever biochemcial means. For this point we're simply concerned with the compound's ability to raise synaptic monoaminergic concentrations over their baseline, and what ratio it does this in.
- Mechanism of action. Is the compund primarily a reuptake inhibitor, or is it a releaser, or is it a mixture - through action at VMAT2, or a different mechanism? What monoaminergic systems does it target, and what ratio do these effects occur in at those systems?
- Adrenoreceptor direct agonism. Does it act directly as an agonist at the different varieties of adrenoreceptor? This becomes even more important if the compound's body distribution is such that it's potential for peripheral effects is high - ie. it doesn't go mostly to the brain. Unfortunately, this isn't often assayed.

Food for thought:
- Desoxypipradrol and 2-benzylpiperidine both feel very similar, very smooth and lacking in peripheral effect, yet 2-benzylpiperidine is almost entirely concerned with NE reuptake inhibition. Perhaps DA action isn't required for a "speedy" effect at all, and that it's actually more concerned with "feel-good" effects and reinforcement.
- Reuptake inhibitors are probably better to look at than releasers when in pursuit for a "clean", "smooth" stimulant. Why? Because their capacity to increase synaptic neurotransmitter concentration and deplete neurotransmitter supplies is less.
- Perhaps we should be looking for primarily-NE-orientated reuptake inhibitors with a CNS-specific action, that are without adrenoreceptor direct agonism, in our pursuits of The Ultimate Stimulant.

 

[ebola?]

Thanks for letting me continue to leach off your knowledge.

>>Desoxypipradrol and 2-benzylpiperidine both feel very similar, very smooth and lacking in peripheral effect, yet 2-benzylpiperidine is almost entirely concerned with NE reuptake inhibition. Perhaps DA action isn't required for a "speedy" effect at all, and that it's actually more concerned with "feel-good" effects and reinforcement.>>

This is interesting. How large is the data set for assays of 2-benzylpiperidine? I would say that "feeling good"/reinforcement is the most desired effect with stimulants. I don't NEED to be more wakeful that badly. Also, I heard hypothesized somewhere (how's that for a non-source source? ) that Strattera works for AD(H)D because much of the dopaminergic reuptake in the frontal corticies actually occurs through NE transporters. Perhaps this is how Nor-epi-centric agents enhance concentration.

>>Reuptake inhibitors are probably better to look at than releasers when in pursuit for a "clean", "smooth" stimulant. Why? Because their capacity to increase synaptic neurotransmitter concentration and deplete neurotransmitter supplies is less.>>

For many people, this doesn't fit with known reuptake inhibitors (eg, coke, methylphenidate, MDPV, Buproprion, etc.), many of which are notorious for making people jittery. Do you imagine this is because of the factors that you note above?

 

[MattPsy]

The assay dataset isn't large for 2-benzylpiperidine, unfortunately.
Here are two references for it:
J Pharmacol Exp Ther. 1979. 210(3):422-8.
J Med Chem. 2007. 50(11):2718-31.

>>This is interesting. How large is the data set for assays of 2-benzylpiperidine? I would say that "feeling good"/reinforcement is the most desired effect with stimulants. I don't NEED to be more wakeful that badly.>>

Yep, feel-good effects are nice, certainly, but we also want to minimize the "fiending" effects that many dopamine-centric stimulant drugs produce. Feel-good and reinforcing don't seem to have to go hand-in-hand.

>>that Strattera works for AD(H)D because much of the dopaminergic reuptake in the frontal corticies actually occurs through NE transporters>>

If you could find the source for this, that would be most appreciated . Interesting theory.

>>For many people, this doesn't fit with known reuptake inhibitors (eg, coke, methylphenidate, MDPV, Buproprion, etc.), many of which are notorious for making people jittery. Do you imagine this is because of the factors that you note above?>>

Yup. Although what i've said is just a very rough theory, haha. Need to do a lot more research on it. Coke is an odd one in this group, as it's effects on ion channels (causing cardiotoxicity) and it's vasoconstricting effects cause some pretty heavy-duty peripheral effects.
Again, I wish adrenoreceptor agonism was assayed more often, as I believe it will be playing an important role. Ephedrine and it's close kin are notorious for their jittery peripheral effects, mediated through this system.

 

[grue]

- Desoxypipradrol and 2-benzylpiperidine both feel very similar, very smooth and lacking in peripheral effect, yet 2-benzylpiperidine is almost entirely concerned with NE reuptake inhibition. Perhaps DA action isn't required for a "speedy" effect at all, and that it's actually more concerned with "feel-good" effects and reinforcement.

As a serious inattentive, I speak for myself and will say that the subjectively zombifying (though concentrative) effects of (it seems) preferential stimulation of norepinephrine are far, far LESS therapeutic for me than brightened mood/increased motivation/confidence/expansive feeling, etc., these effects indeed being linked to dopaminergic activity in the nucleus accumbens.

Reuptake inhibitors are probably better to look at than releasers when in pursuit for a "clean", "smooth" stimulant. Why? Because their capacity to increase synaptic neurotransmitter concentration and deplete neurotransmitter supplies is less.

Neurotransmitter depletion just doesn't happen with therapeutic dosages of amphetamines.

 

[ebola?]

>>
Yep, feel-good effects are nice, certainly, but we also want to minimize the "fiending" effects that many dopamine-centric stimulant drugs produce. Feel-good and reinforcing don't seem to have to go hand-in-hand.>>

well, to me, fiending usually goes along with states worth fiending for. Also, where does feeling good disconnect from triggering the dopamine reward pathway, talking just talking about drugs...well besides with psychedelics?

 

[negrogesic]

^^^Keep in that mind there are a number of drugs that people (and primates) will "fiend" for, but are not particularly recreational. Even in respect to humans, I think it is entirely possible for someone to want something that they don't like.

The following article proposes that the subjective high of stimulants may be a product of NE, as many of the popularly abused stimulants are more potent releasers/inhibitors of NE than they are of dopamine. I think they refered to this as the "noradrenergic hypothesis". So while dopamine is without question linked to reinforcing behavior, NE may be associated with liking (as opposed to wanting).

This is the abstact:

A large body of evidence supports the hypothesis that mesolimbic dopamine (DA) mediates, in animal models, the reinforcing effects of central nervous system stimulants such as cocaine and amphetamine. The role DA plays in mediating amphetamine-type subjective effects of stimulants in humans remains to be established. Both amphetamine and cocaine increase norepinephrine (NE) via stimulation of release and inhibition of reuptake, respectively. If increases in NE mediate amphetamine-type subjective effects of stimulants in humans, then one would predict that stimulant medications that produce amphetamine-type subjective effects in humans should share the ability to increase NE. To test this hypothesis, we determined, using in vitro methods, the neurochemical mechanism of action of amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), (+)-methamphetamine, ephedrine, phentermine, and aminorex. As expected, their rank order of potency for DA release was similar to their rank order of potency in published self-administration studies. Interestingly, the results demonstrated that the most potent effect of these stimulants is to release NE. Importantly, the oral dose of these stimulants, which produce amphetamine-type subjective effects in humans, correlated with the their potency in releasing NE, not DA, and did not decrease plasma prolactin, an effect mediated by DA release. These results suggest that NE may contribute to the amphetamine-type subjective effects of stimulants in humans.
http://www.ncbi.nlm.nih.gov/pubmed/11071707