Stimulants of the Future II

[ebola?]

Does the drug remain non-neurotoxic if it's administered with a DA releaser?

I thought the reason MDAI was non- neurotoxic was because as a 5HT releaser, it was devoid of DA releasing properties, but when the two were combined, you got the neurotoxicity.

Theoretically, combination w/ a DA releaser should be neurotoxic. Someone should check with biopsied and autopsied rats though.

IIRC, Nichols found a combination of a selective 5ht releaser and a DARI to be non-neurotoxic...at least to the extent that he found M1 to be.

Could it be that M1 primarily releases 5ht but acts as an RI at DA?

IIRC, bilzor claimed that DARIs max out at around 500% percent 'normal' levels of intersynaptic DA, releasers at 800%, so it makes sense.

ebola

 

[TheAzo]

I thought that generally the cathinones acted as DARIs while the amphetamines were DA releasing agents.

 

[dread]

IIRC, Nichols found a combination of a selective 5ht releaser and a DARI to be non-neurotoxic...

True, but the DARI used in that study was not a typical DARI... IIRC..

I think it was GBR-something but I'm not sure... should find that study somewhere...

 

[/navarone/]

So what you guys are saying is that simple DA releasing causes neurotoxicity? Why?
I'm gettin really confused when comparing DRI to DA releasers...

 

[N0 W4RN1NG]

So what you guys are saying is that simple DA releasing causes neurotoxicity? Why?

When combined with 5HT release, some excess dopamine will inevitably get taken up by serotonergic neurons, resulting in damage.

This is why things like MDMA are neurotoxic.

 

[ebola?]

I thought that generally the cathinones acted as DARIs

Aye, but this actually isn't true of M1 or even methcathinone.

ebola

 

[/navarone/]

When combined with 5HT release, some excess dopamine will inevitably get taken up by serotonergic neurons, resulting in damage.

This is why things like MDMA are neurotoxic.

I guess this would happend with with 5-HT RI as well....

This sucks

 

[MeDieViL]

3 methylmethcathinone.

Would this work? How would the changing the methyl group from the 4th position to the 3th position affect serotonin release?

 

[c0rt3x]

Interresting question^^. I guess yes, it could do so - but I cant tell you for sure.

 

[dread]

How would the changing the methyl group from the 4th position to the 3th position affect serotonin release?

I would wager it will make the chemical more dopaminergic.

 

[/navarone/]

Probably, the changes are similar to those of 3-MA.

Not much info on that either.

 

[MeDieViL]

Probably, the changes are similar to those of 3-MA.

Not much info on that either.

Balanced ratio of monoamine release, thats pretty interesting, also because the methyl group is on the 3th position it should metabolize in a differend way then mephedrone (if i'm correct) so it shouldnt have the same metabolite issues.

 

[fastandbulbous]

^ You'll still get some 3-methylephedrine produced - quite how toxic that is, I don't know

 

[c0rt3x]

I'm wondering why there are still no 4-Methylaminorex derivatives on the RC market.

What about the 4-MAR analog of Clominorex:

Or maybe additional methylation just like the mephedrone analog of it. I think it was worth trying those modifications

 

[/navarone/]

That makes me think of how 4-MAR would be without that 'weird' NH2 on top.
Any guesses?

 

[dread]

4-MAR without the imine? Kinda like phenmetrazine with a 5-ring instead of 6-ring?

I don't know, I guess it could be worthwhile...

I wonder if it has been made ever?

 

[ebola?]

Or maybe additional methylation just like the mephedrone analog of it.

What's the SAR like for the Aminoreces? I know that it's not like phenethylamines. . .

ebola

 

[/navarone/]

4-MAR without the imine? Kinda like phenmetrazine with a 5-ring instead of 6-ring?

I don't know, I guess it could be worthwhile...

I wonder if it has been made ever?

No not the imine (=N-), but the weird amine (-NH2) group on top of the imine
(kind of like phenmetrazine but with a 5 member ring and the iminne double bond).
Actually the imine thing inspires me, I always wondered how they behave compared to tertiary amines, in fact I used to ponder about the potential pharmacological differences between methamphetamine and n-methyleneamphetamine.

Wikipedia make imines seem uncredibly unstable, stating that they can hydrolyse with water and react with amines to form amidals. Though i find it hard to belive that they are sooo unstable since our body (eg. DNA) is full of vital molecules containing imines.

 

[/navarone/]

Very large.
| ''' Compound ''' || '''NE Release''' || '''NE Reuptake''' || '''5-HT Release''' || '''5-HT Reuptake''' || '''DA Release''' || '''DA Reuptake'''
|-
| [[Aminorex]] || 26.4 ± 2.8 || 54.5 ± 4.8 || 193 ± 23 || 1,244 ± 106 || 49.4 ± 7.5 || 216 ± 7
|-
| [[Chlorphentermine]] || >10,000 || 451 ± 66 || 30.9 ± 5.4 || 388 ± 6 || 2,650 ± 273 || 3,940 ± 110
|-
| [[Phentermine]] || 39.4 ± 6.6 || 244 ± 15 || 3,511 ± 253 || 13,900 ± 510 || 262 ± 21 || 1,580 ± 80
|-
| [[Amphetamine|(+)-Amphetamine]] || 7.07 ± 0.95 || 38.9 ± 1.8 || 1,765 ± 94 || 3,830 ± 170 || 24.8 ± 3.5 || 34 ± 6
|-
| [[Methamphetamine|(+)-Methamphetamine]] || 12.3 ± 0.7 || 48.0 ± 5.1 || 736 ± 45 || 2,137 ± 98 || 24.5 ± 2.1 || 114 ± 11

Remember, the lower the value the more potent it is at that.
see: http://www.xr.com/bind

Sorry, simple question, what does SD stand for?

 

[nuke]

The IC50s and binding affinity comparison relative to specific substrates is wildly different as compared to the above quoted affinity values, however. See:

A Comprehensive In Vitro Screening of d-, l-, and dl-threo-Methylphenidate: An Exploratory Study

dl-Methylphenidate (MPH) has been widely used to treat attention-deficit/hyperactivity disorder (ADHD) for the last half century. It had been exclusively available in the racemic form, i.e., a 50:50 mixture of d- and l-isomers. However, a single enantiomer formulation, d-MPH (dexmethylphenidate), became available for general clinical use in 2002. For this reason, the intrinsic pharmacological differences in the effects of d- and l-MPH have recently come under intense investigation. The primary therapeutic effects of MPH are generally recognized to reside in the d-isomer. The present investigation provides quantitative values for a broad range of receptor-level interactions of the individual MPH isomers to better characterize the distinction between dl-MPH versus d-MPH versus l-MPH as it relates to binding affinity at sites associated with relevant central nervous system (CNS) pharmacology, as well as peripheral physiology. Overall, there were few differences in binding affinities between d-MPH and the racemate whereas there were more apparent differences between d-MPH and l-MPH. d-MPH exhibited prominent affinity at the norepinephrine transporter (NET) site, even exceeding such affinity at the dopamine transporter (DAT). These results further demonstrate that affinity for catecholaminergic sites largely resides in the d-MPH isomer. Although binding affinity was not demonstrable at the serotonin (5-HT) transporter site (SERT), novel findings of the study included affinity for the 5-HT1A and 5-HT2B receptor sites for both d- and l-MPH, with d-MPH exerting by far the most predominant effects at these sites. Thus, the emerging data of favorable therapeutic effects of ADHD treatment with d-MPH (and dl-MPH) may be underpinned by affinity and potential pharmacologic effects at NET and DAT sites, as well as sites relevant to serotonergic neurotransmission that may modulate mood, cognition, and motor behavior. However, the present exploratory studies reflect receptor binding affinities only. The specific pharmacological activities (i.e., agonism vs. antagonism) of these compounds await further exploration.

The full text is free, and you'll see that the affinity for NET inhibition appears to be many fold greater than that for DAT inhibition.