Stimulants of the Future III

[Hammilton]

Binding affinities have nothing to do with potency by the way.

Were you high when you wrote this? Of course they do. In fact, they're one of the more important aspects related to potency. Other factors are BBB penetrability and rate of metabolism, but binding affinity is inextricably linked to potency.

 

[/navarone/]

^^ I thought so too.

BTW, wold you consider a triple reuptake inhibitor (like dichloro-JNJ-7925476) with such values:

MA(mg/kg): 0.39
ptosis(mg/kg): 0.14
DA(nM): 0.99
NE(nM): 0.68
5-HT(nM): 1.8

A good drug?

 

[vecktor]

ptosis meaning reversal of reserpine or tetrabenazine ptosis?

 

[/navarone/]

Don't ask me, I thought you would know....LOL
Check my JNJ link above.

 

[ebola?]

To each is own of course.

Indeed. I find MPH taken rectally or insufflated to be as problematic as that taken orally. The sole exception would be how careful combination of MPH and selegiline feels good to me, like d-amp only even 'cleaner'.

ebola

 

[Enkidu]

Have there been any subjective reports or bioassays of this compound (GBR12935)

AFAIK, GBR12935 is not recreational. Some of the other compounds in that series might be.

 

[fastandbulbous]

This one seems interesting.

http://en.wikipedia.org/wiki/LR-5182

LR-5182 has two stereoisomers, both of which are active, although one isomer only blocks reuptake of dopamine and noradrenaline, while the other blocks reuptake of serotonin as well.

I'd love to try it.

There's a thesis paper (I have a copy somewhere) on the topic of inhibitors of DAT and some have three carbons between the aryl group and the amine. Apparently they still fulfil one of the requirments discovered, in which the only really important thing is the distance of the delocalized aryl ring and the amine function. There were even a couple of phenoxyethylamine derivatives (mostly involving strained or similarly twisted rings). Basically see cocaine and the fact it's not a PEA derivative - now that's about the greatest deviation from the PEA model that I've seen (a whole shitload of carbons and an oxygen between the aryl group and the amine)

 

[dread]

Were you high when you wrote this? Of course they do. In fact, they're one of the more important aspects related to potency. Other factors are BBB penetrability and rate of metabolism, but binding affinity is inextricably linked to potency.

I should have been more specific... what I meant was, binding affinities are not synonymous to potency. There are ligands with high binding affinities which have low potency or efficacy.

Basically see cocaine and the fact it's not a PEA derivative - now that's about the greatest deviation from the PEA model that I've seen (a whole shitload of carbons and an oxygen between the aryl group and the amine)

Yeah cocaine is a puzzling molecule, in the viewpoint of the PEA model. Sure, phenylpropylamines are understandable since they're only 1 more carbon. But cocaine actually has an ester group between the aryl and amine. Which also gives it local anaesthetic properties. Anyway that's 5 atoms between the phenyl and the amine, which goes to show DA transporter is not very picky as to it's ligands...

 

[Hammilton]

I should have been more specific... what I meant was, binding affinities are not synonymous to potency. There are ligands with high binding affinities which have low potency or efficacy.

Right. Efficacy is unrelated to affinity. High efficacy, close to 100% means the drug is an agonist, lower efficacy a partial agonist, no efficacy an antagonist, negative efficacy, an inverse agonist (I think I have this last one right, please correct if I'm wrong).

Buprenorphine has high affinity but reduced efficacy. It's still a pretty potent drug though, substantially more potent than morphine, even with reduced efficacy.

Yeah cocaine is a puzzling molecule, in the viewpoint of the PEA model. Sure, phenylpropylamines are understandable since they're only 1 more carbon. But cocaine actually has an ester group between the aryl and amine. Which also gives it local anaesthetic properties. Anyway that's 5 atoms between the phenyl and the amine, which goes to show DA transporter is not very picky as to it's ligands...

I don't think there's really a phenethylamine "model" for DAT inhibitors. There are definitely lots of phenethylamines that are DAT inhibitors, but an amine group seperated from an aromatic group by two carbons happens to work out pretty good, making for a wide range of PEA derivatives with DAT affinity.

With Cocaine, Clofencyclan, Dimethocaine and GBR12935, energy minimized, an amine group is roughly in the same location relative to the aromatic group.

I've taken these groups, plus BTPC, MM2 minimized, and measured the distances of amine to carbons of the aromatic ring, to the H-bond acceptor, and the distances from H-bond acceptor to the carbon atoms of the aromatic ring. They're all pretty close (I haven't finished all the math yet) but there's obviously a bit of deviation, as most of these are fairly flexible.

But then again, the amine isn't even a requirement. Analogues of cocaine and methylphenidate with the amine replaced by carbon or oxygen atoms are known and active and have fairly high affinities. I don't know if it's really promiscuity or just misunderstanding on our part of how the molecule is actually binding. Is the amine actually taking part in H-bonding or salt bridge formation, or is it just space filling? With DAT inhibitors it seems that it's just space filling.

 

[Smyth]

did u guys even touch tranylcypromine yet?

 

[Enkidu]

Anyway that's 5 atoms between the phenyl and the amine, which goes to show DA transporter is not very picky as to it's ligands...

Not exactly, there are multiple binding sites for inhibitors and possible overlap between some sites.

 

[fastandbulbous]

The binding affinities are amazing. NET Ki = 277, SERT Ki = 289, DAT Ki = 4.90. I've seen these selective DAT inhibitors before, but never the numbers. Unbelievably potent and selective for dopamine. Cocaine's DAT inhibition is comparitively extremely weak (DAT Ki = 478 ) and extremely nonselective (SERT Ki = 304, NET Ki = 779 ).

I suppose that this compound will have very euphoric almost sedating effects, similar to what some people experience from insufflated methylphenidate, NET Ki = 118, DAT Ki = 90.2 (the lower the Ki the more potent inhibition).

Those numbers mean nothing without units (yes I know they're nM, but you have to say it for people who don't otherwise they could just as easily mean elephants or cheese scones)

 

[mr shush]

chinese scones lol

Ah cheese scones not chinese hummm

 

[Hammilton]

Not exactly, there are multiple binding sites for inhibitors and possible overlap between some sites.

I've been reading lots of these papers, and I don't see much evidence for this. Cocaine and DA bind to the same site, even.

Some ligands seem to bind at a slightly different site, though. Mazindol analogues selective for DAT have been prepared, but they still seem to be relatively non-recreational.

The key with the recreational value of DAT inhibitors is the ratio of ki to EC50 (I think I express this right, it's the ratio of affinity to DA inhibition). mazindol has a highish affinity, but low DA inhibition.

The ability to dissociate the two is key, and was the driving force behind the search for a cocaine antagonist.

 

[fastandbulbous]

Wasn't diphenylprolinol once touted as a suitable drug to both replace cocaine (only mild activity in comparison) & stop it binding if taken?

 

[Coolio]

Wasn't diphenylprolinol once touted as a suitable drug to both replace cocaine (only mild activity in comparison) & stop it binding if taken?

I hope not. That stuff makes me paranoid unlike any other stimulant I've tried.

 

[MurphyClox]

What about 4-trifluoromethylamphetamine?

I read in JPET 2004, 308, p.679 that the Ki for hSERT is 5.2µM (for comparison: in the same assay 0.83µM for MMAI, 1.1µM for MDA), or in JPET 2008, 325, p.791 a Ki for hSERT of 600nM (here MDA got 700nM, so practically the same value). Well, different assay, different value, but still in comparable range.
Apart from this, further peer-review information is scarce...

Was this ever tested in humans before?
What do we expect as activity?

I'm fully aware that the experiences with other amphetamines that were substituted solely in position 4 of the ring were not the best (neurotoxicity shown for 4-Cl, and 4-Me). But a forum is for discussion!

Opinions?

- Murphy

 

[dread]

How about 4-cyanoamphetamine? Has that ever been tested?

At least that one would be relatively easy to make from PBA...

 

[Enkidu]

I've been reading lots of these papers, and I don't see much evidence for this. Cocaine and DA bind to the same site, even.

Some ligands seem to bind at a slightly different site, though. Mazindol analogues selective for DAT have been prepared, but they still seem to be relatively non-recreational.

Yes, I think I have to retract my statement. To quote vecktor "there are at least two sites on DAT...." and I thought that he meant there are two sites for inhibitors, but I think he was just talking about one site for the inhibitor and another for a substrate.

However, it does seem that, as both of us stated, DAT 'ligands' (either substrates or inhibitors or both) have overlapping binding (i.e., non-identical) sites on the transporter.

 

[Hammilton]

Yeah, I think perhaps that those with high affinity but low reuptake inhibition must bind in such a way that DA is still able to reach it's normal pocket (or a portion thereof)?



Anyway, as a personal interest of mine, alpha-cyclohexyl-PEA's, I've come across papers that show that these are fairly potent stimulants.

@ 3mg/kg alpha-cyclohexyl-N-ethyl-PEA increased spontaneous motor activity about 500%
@ 10mg/kg it raised it more than 1000%

methamphetamine
@ .1mg/kg increased it a bit more than 100%
@ .3mg/kg increased about 700%

Significantly less potent, but the indicators of a recreational stimulant on par with methamp were found. Also, they had favorable LD50s.