Stimulants of the Future

[mad_scientist]

CFT is 7x the potency of cocaine (in rats at least), but much longer lasting;

Norman AB, Buesing WR, Norman MK, Tabet MR, Tsibulsky VL. The self-administration of WIN 35,428 and cocaine: comparisons of satiety threshold and elimination half-life in rats. European Journal of Pharmacology. 2004 Jan 12;483(2-3):281-7.

Pseudotropyl 4-fluorobenzoate is the analogue of cocaine with the 2-COOCH3 group removed and the benzene ring substituted with fluorine at the 4-position, so similar to CFT in some ways but much less potent.

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5147770

 

[hussness]

Intramolecular H-bonding in phenyltropane and methylphenidate DRIs

I have recently read and thought a bit about the intramolecular H-bonding theory that attempts to unify the SARs of methylphenidate and phenyltropane cocaine analogs, and have drawn some structures. I was wondering if anyone would mind checking them and commenting on whether or not they are consistent with the theory.

 

[fastandbulbous]

CFT is 7x the potency of cocaine (in rats at least), but much longer lasting;

Norman AB, Buesing WR, Norman MK, Tabet MR, Tsibulsky VL. The self-administration of WIN 35,428 and cocaine: comparisons of satiety threshold and elimination half-life in rats. European Journal of Pharmacology. 2004 Jan 12;483(2-3):281-7.

Pseudotropyl 4-fluorobenzoate is the analogue of cocaine with the 2-COOCH3 group removed and the benzene ring substituted with fluorine at the 4-position, so similar to CFT in some ways but much less potent.

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5147770

May be 7x the potency in rats, but from personal experience with CFT ( had 500mg given asd a gift from a friend to 'play around with') it's at most 2x the potency of cocaine ih humans and is qualitatively different in feel (more like methylphenidate in feel), being less euphoric.

While less potent in terms of dose required (25mg of fluorotropacocaine vs. 5mg of CFT), fluorotropacocaine felt very cocaine-like. From people I know who've also had both and are fans of cocaine (I'm not), CFT was not seen as a suitable replacement whereas some preferred fluorotropacocaine to their street bought coke...

 

[LuxEtVeritas]

FnB had intimated CFT at 1/3 C and i was asking what ratio of potency is CPT to C, not what it was (or trying to commuinicate that ,LOL)

also i see now he has noted perhaps at most 2x potency of C in humans

anyway it also appears to not be as 'good' qualitative to aficionados i guess

also what is the ratio of TropaC to FlurotropaC?

 

[Thanatopium]

4-MAR is long acting to say the least, and takes a heavy toll on the body IMHO. Plain old aminorex should be rated as far more euphorigenic than methamp or even cocaine. Body rushes, the works.

There is a strange "flavor" to these compounds... The serotonergic effects are terrifying. VERY subtle at first, OCD behavior begins, ending in a completely pathological schizotypal state the user is completely unaware of.

I would not hesitate to say that they are smart drugs in the truest sense of the word. But the same effects that make them nootropic at low doses and well maintained rate of ingestion become the elements of the psychosis...

Intuition of interconnected concepts, sensitivity to the moods, emotions, and intentions of others, laser like mental focus...

Easily I would say they have more of an elemtn of risk than methamp, because even the most self aware, educated user is taken off guard...

A beautiful, terrifyingly seductive set of compounds.

 

[bupropion]

Also, I dug up an old (2003) review article by Rothman & Baumann (link below) that had EC50 values of neurotransmitter release (not reuptake, but truly release) for a number of phenethylamines (all in nM):

Phenethylamine: 5-HT; NA; DA

(d)-amphetamine: 1765; 7.07; 24.8

(d)-phenmetrazine: 3246; 37.5; 87.4

(d)-methamphetamine: 736; 12.3; 24.5

(d)-fenfluramine: 51.7; 302; 10000

(dl)-MDMA: 56.6; 77.4; 376

Rothman & Baumann (2003). Eur. J. Pharmacol. 479: 23-40.

Do you have the EC50 values for methylphenidate, cocaine, meth/cathinone, and any of the stimulant diet drugs for comparison?

Edit: I found a chart but it doesn't have values for methylphenidate, methcathinone, mephentermine or 4-methylaminorex, norpseudoephedrine or MDPV. Also it gives extremely high values (>10,000) across the board for diethylpropion (?).

 

[bupropion]

What would amphetamine with a double bond to the methyl carbon do? Is there any possibility it would be stronger?

 

[Ham-milton]

You're really interested in really tiny changes to the structure.

Doubt it'd be stronger.

 

[haribo1]

What would amphetamine with a double bond to the methyl carbon do? Is there any possibility it would be stronger?

It would be an imine which is a)much less basic & b)is unstable.

 

[Riemann Zeta]

What would amphetamine with a double bond to the methyl carbon do? Is there any possibility it would be stronger?

You mean this? I think it would be inactive, considering the conformational lock that an sp2 carbon engenders. Also, it would be pretty unstable; it would polymerize rather quickly. Might be a good synthetic plastic.

 

[Smyth]

Olefinic alkaloids

It's actually called an olefin, an imine is the name for when the double bond is connected to the nitrogen.

Im not sure if it would be that stable, but it's related to F&B's original proposal for PEA-based psychedelic.

The N-benzyl psychedelics have incredibly potent in vitro activity.

You'd also have to think about how this olefinic compound could be made. In the synthesis of selegiline the α-carbon originally starts life as:

Carboxylic acid -> 1° alcohol -> alkyl-chloride -> methyl

F&B's original proposal actually was for compounds possessing a β-methylene functional group, before anybody tries to correct me.

However, in order for the terminal olefin to be relatively chemically/metabolically stable then it must be conjugated to something, such as an oxgen in the specific case of the allyloxy group.

A vinyl group stuck connected to a phenyl ring is okay though because of the resonance with the aromatic electrons.

 

[Pomzazed]

Oops, double bond at that position will quickly undergo tautomerization from its enamine form to the more stable imine form.

where in the condition where water is present, the imine would be further hydrolyzed to 1-phenylpropan-2-one and ammonia.

 

[Holy_cow]

In the synthesis of selegiline the α-carbon originally starts life as:

Carboxylic acid -> 1° alcohol -> alkyl-chloride -> methyl

Selegiline is nowadays exclusively made from ephedrine, which has the advantage of being stereospecific.

 

[bupropion]

Isn't the ephedrine sold in stores the l-isomer and pseudoephedrine the d-isomer? Could d-deprenyl be synthesized by starting with Sudafed? What about adding a hydroxy group at the beta position to selegiline, then synthesizing d-deprenyl from that?

 

[Smyth]

Pomzazed, good observation my friend! I had entirely overlooked that simple yet entirely fundamental bit of organic chemistry. Well spotted!

I have a paper on d-selegiline somewhere. Due to the fact that it is metabolized to the active isomer of meth, they wanted to see what the abuse value of this was like, comparing to the levo-isomer.

The synthesis from L-phenylalanine is also completely stereospecific too. I dont judge selegiline to be a worthwhile drug imo. Some guy said his friend was taking Emsam and found it helpful. Selegiline is cheap though, its just the customs charge (£12) meant my original order including delivery (£18 ) meant that it almost doubled in price. I thought it was a big let-down, since I had got quite high hopes that a compound which increases the amount of neuronal dopamine would be a very worthwhile substance, especially given its high potency. However, I stopped taking it before even getting half-way through my script of 100 tablets.

 

[fastandbulbous]

Isn't the ephedrine sold in stores the l-isomer and pseudoephedrine the d-isomer? Could d-deprenyl be synthesized by starting with Sudafed? What about adding a hydroxy group at the beta position to selegiline, then synthesizing d-deprenyl from that?

l-ephedrine & d-pseudoephedrine both have the same stereochemistry surrounding the carbon with the amine group (both get reduced to d-methamphetamine). Deprenyl has the opposite stereochemistry about the amine carbon (it's metabolites are l-methamphetamine & l-amphetamine) so they'd start with d-ephedrine or l-pseudoephedrine)

 

[bupropion]

Oops, double bond at that position will quickly undergo tautomerization from its enamine form to the more stable imine form.

where in the condition where water is present, the imine would be further hydrolyzed to 1-phenylpropan-2-one and ammonia.

Would the imine form be active? How much so?

\/ Oops, sorry for not reading/thinking at the time.

 

[vecktor]

Would the imine form be active? How much so?

the answer is in the bottom part of the post you quoted above.

 

[<pyridinyl_30>]

P2P is not active.

 

[Vivian]

I wish this thread could be translated for people who are not chemists.