Can DAT ligands be selective for central but not peripheral DAT like enantiopure DRA?

[Nagelfar]

What would this take? Could certain reverse esters of TMP do this? or do the S active enantiomers of DRIs have this ability? or neither, and if neither, is it even possible?

What I here mean is the peripheral stimulation, racing heart, non-CNS locomotor increase, from substances like l-methamphetamine, that do not affect the euphoria of d-methamphetamine and separating them similarly for cocaine and methylphenidate type drugs.

Is there a similar conformation among reuptake inhibitors that would prevent their attaching as ligands to the same peripheral transporters? If entry through the reuptake pump is the mechanism of action by which DRAs function, and the difference between racemic and single stereo-isomers can prevent ones effect on one or another of the two classes of specific transporters, a person would venture to guess that binding ligands to the same sites could be likewise wafted to just one or another as targeting that type of binding selectively to the exclusion of the other.

Could anyone provide me with any substance, or possibility of evidence for this phenomena in the class of drugs I am referencing?

 

[Wizzle]

If such a drug existed I assume it would be a goldmine as an AD(H)D drug. I would love to have it instead of methylphenidate. The problem is that you cannot use the blood brain barrier to selectively target the CNS instead of the PNS.

I do believe that l-meth is just a crappy stimulant, all epinephrine and almost no dopamine, it is however a CNS-stim too.

 

[sekio]

There is no "central" and "perhipheral" DAT, there's just the DAT protien. (There are not 2 transporter protiens.) Whether or not the cells are behind the blood-brain barrier decides whether it's "central" or not. If there was an entirely different set of monoamine transporters for nerve cells then the world of drugs would be very different.

I think it's a bit of a mistake to view stimulants as "central" or "perhipheral" - in general the side effects come from an excessive level of monoamines, and/or adrenergic/serotonergic 5-HT2C activity (undesired receptor activity modulating blood pressure, anxiety, etc...). Personally I think the issue at hand is the ratio of norepinephrine release to dopamine.

 

[Nagelfar]

There is no "central" and "perhipheral" DAT, there's just the DAT protien. (There are not 2 transporter protiens.) Whether or not the cells are behind the blood-brain barrier decides whether it's "central" or not. If there was an entirely different set of monoamine transporters for nerve cells then the world of drugs would be very different.

I think it's a bit of a mistake to view stimulants as "central" or "perhipheral" - in general the side effects come from an excessive level of monoamines, and/or adrenergic/serotonergic 5-HT2C activity (undesired receptor activity modulating blood pressure, anxiety, etc...). Personally I think the issue at hand is the ratio of norepinephrine release to dopamine.

This being the case, could someone show me the difference between the selectivity affinity for NET, DAT & SERT of levo-meth as against dextro-meth to confirm this?

 

[ebola?]

Could there be stereoselectivity for central vs. peripheral effects if a hypothetical drug entered the brain via active transport only, one of the isomers holding greater affinity for the transporter than the other?

I recall Negrogesic saying that l-meth has binding affinities like phentermine's...so it seems like shit you could extract from Vicks should be less crappy than it is.
...
And, yes, it follows that maximum 'selectivity' for CNS effects would lie at maximal rate of diffusion across the BBB.


ebola

 

[sekio]

According to here,

D-(+)-Methamphetamine NET release EC50: 12.3 ± 0.7 DAT release EC50: 24.5 ± 2.1 SERT release EC50: 736 ± 45
L-(–)-Methamphetamine NET release EC50: 28.5 ± 2.5 DAT release EC50: 416 ± 20 SERT release EC50: 4,640 ± 243

L-meth is far more selective for NET which produces more "peripheral" effects vs "central" dopamine-mediated effects. It is comparable to "super pseudoephedrine".

 

[ebola?]

Oh my. Is phentermine that shitty?

ebola

 

[sekio]

Yes, yes it is.

 

[Nagelfar]

According to here

Wow. At #5, Look at how much more affinity Cocaine has for serotonin over MDMA. I knew it was more, but I didn't realize it was *that* much more. Blows to pieces (no pun intended) all of those ravers who speak of the evils of cocaine as a "dopamine drug* over the 'healthiness' of the neurotoxic Ecstasy as a "serotonin drug"

 

[ebola?]

er...reuptake inhibition at 5ht is very different from release. Coke is hardly entactogenic and doesn't feel that different from DARIs lacking 5ht affinity.

ebola

 

[Nagelfar]

er...reuptake inhibition at 5ht is very different from release. Coke is hardly entactogenic and doesn't feel that different from DARIs lacking 5ht affinity.

ebola

I beg to differ. Coke is way more cleanly empathetic feeling than say, meth, esp. when comparing them both as IV'd. To me: meth feels less clear headed, as MDMA also feels, but without the empathy of MDMA, while coke feels clear headed with aspects of both MA (the 'interest' & stimulation) & MDMA (the cozy connected empathy) but without the duration of either.

 

[sekio]

For receptor affinities, bigger is not neccesarily better - smaller numbers = more potent drugs. And as ebola stated, comparing a releasing agent and a reuptake inhibitor is kind of like comparing apples to oranges.

 

[ebola?]

I beg to differ. Coke is way more cleanly empathetic feeling than say, meth, esp. when comparing them both as IV'd. To me: meth feels less clear headed.

I find meth way more empathogenic and clearer headed than cocaine. Odd. I have never tried IV routes though.

ebola

 

[Nagelfar]

For receptor affinities, bigger is not neccesarily better - smaller numbers = more potent drugs. And as ebola stated, comparing a releasing agent and a reuptake inhibitor is kind of like comparing apples to oranges.

I agree with the apples to oranges, as I state about my subjective experiences. But I assume you haven't looked at the link, the numbers were smaller by many multitudes (SERT: Cocaine = 0.74 ± 0.03, MDMA = 2.41 ± 0.73), not larger, why would you assume I thought larger?

I find meth way more empathogenic and clearer headed than cocaine. Odd. I have never tried IV routes though.

ebola

Cocaine is just jittery and meth more smooth any other route than IV, so I can see why you say that. Which is why I noted "IV" as the (in my opinion) purest route of a drug due to bioavavailability, speed of onset, and less time in prior peripheral activity.

 

[sekio]

Sorry, I was looking at section 1 and not 5.

 

[negrogesic]

Methamphetamine is without doubt, more empathogenic than cocaine. This is a generalization, but individuals who abuse cocaine may appear talkative and sociable initially, but tend to be very self-focused (particularly as one begins the comedown descent). Methamphetamine users will often call old friends, relatives etc and express what seems to be concern/interest/good-will (etc) towards others (particularly those new to the drug). That being said, I prefer high quality cocaine to crystal meth (or other amphetamines and agents of similar mechanism). Plus, cocaine does not possess nearly the same degree of neurotoxicity (ever meet an individual who has abused meth for over a decade.......their prognosis is poor even upon cessation). But a comparison of these two very different drugs, is as mentioned, pointless for this discussion.

There are some extremely potent and specific DAT ligands, but these "unbalanced" compounds lack the recreational value of less potent compounds. Do not let the numbers fool you; while not particularly "potent" on paper, cocaine is a very "well-balanced" compound (DA:NE:5HT)

 

[ebola?]

Well put. Tastes seem to vary a lot as to preference for meth vs. coke (I'm lucky in that dexedrine feels damned close to meth for me but is far less neurotoxic).

Would a highly selective DAT ligand with a rapid onset be a good candidate for good recreation? Can we expect releasers more selective for DA in the future?

ebola

 

[sekio]

You want a fast-acting selective DAT ligand? ask an IV methylphenidate user. MPH is more selective for DAT over NET, but I still have a feeling too much DA activity would lead to psychotic behavior a la MDPV.

 

[pofacedhoe]

DA releasers for me feel very scattered and paranoia laden but euphoric yet with brutal comedowns (methylone, amphetamine, methamphetamine, MDMA, mephedrone), while DRI's are often mellow and relaxing with mild comedowns (cocaine,methylphenidate, MDPV, buphedrone) that last hours instead of days. empathy is related to the severity of the euphoria! whichever makes you personally the most euphoric by a mile would be the stim that creates more empathy in your early days of usage. serotonin is involved though, maybe if enough dopaminergic effects have occurred later in a binge a lá MDPV

 

[fastandbulbous]

According to here,

D-(+)-Methamphetamine NET release EC50: 12.3 ± 0.7 DAT release EC50: 24.5 ± 2.1 SERT release EC50: 736 ± 45
L-(–)-Methamphetamine NET release EC50: 28.5 ± 2.5 DAT release EC50: 416 ± 20 SERT release EC50: 4,640 ± 243

L-meth is far more selective for NET which produces more "peripheral" effects vs "central" dopamine-mediated effects. It is comparable to "super pseudoephedrine".

As my old physics teacher used to say to me "units, boy. Units" I know it's nM, but without units it could be elephants, miles per hour etc. Sorry to be pedantic, but said teacher had a big influence on me (and besides I've just had a dose of amphetamine)!