lefetamine analogues

[wungchow]

lefetamine

here's some hybridized structures of lefetamine, that may be less neurotoxic & possibly more active at both DAT as well as u-opioid receptors. took structural features from methylphenidate, desoxypipradrol, and pethidine.

 

[Adrenochrome]

hmmm
....
what makes u think tehse are less neurotoxic?
although I do believe that lefetamien could be a lot more potent so they could possibly have higher affinities for monoamine transporters,
how would the fellows in ADD increase the affinity for µ opiod receptors?

 

[Adrenochrome]

what would happen if we substitued the amine of amphetamine with Piperidine ring?

 

[Refluxer]

All those suggested structures lock up one of the phenylgroups with a bridge. Have you gone through structures of the different classes to see if that is a good thing (depending on what kind of activity you want)? The fixation will really reduce the structures freedom of movement, which can lead to a good match and high potency, but if it's not the right match it will likely be a bad thing activitywise.

 

[Refluxer]

Adrenochrome: Compare with other alkylsubstituted amphetamines. In general reduced activity is to be expected. I read a paper on direct amination of olefines where the writer had the compound you describe as an example.

 

[mad_scientist]

I think an m-hydroxy on the phenyl ring would be a must to improve mu opioid affinity, I guess the one further away from the nitrogen would be the correct one? Not sure what conformation lefetamine binds in.

Also you could play around with different alkyl substitutions on the nitrogen and try different aromatic rings on the alpha-aryl group. Hard to guess what kind of changes would be good without having seen any SAR studies, I'm not even sure how lefetamine was discovered or who by, its quite an old drug and all the original papers about it seem to be in Italian...

 

[fastandbulbous]

^ Well 'borrowing' your above structure & modifying it ( & rotating) should make it a lot more interesting. If you view the benzyl group as a very flexible cyclohexyl ring, you can see where the NMDA antagonist activity comes from - the 2-chloro group is that seen in ketamine. It appears that the 2-chloro group helps with the warmth and possibly psychedelic properties as plain unsubstituted phenyl ring compounds are a bit less engaging (friend's description) and a 2-thienyl group produes basic, industrial strength ketamine like effect that has none of the airs, graces or subtleties of ketamine - brutish might help describe it's effects

 

[Adrenochrome]

All we got to do is patent these and form a Pharma and get an NDA application

 

[wungchow]

mad scientist:

i think adding a hydroxyl group would definitely improve mu-opioid binding but in general -OH groups on the phenyl ring makes the compound into a crap DAT inhibitor.

f&b: i think it would definitely be possible to make a combination NMDA antagonist, DAT blocker, mu-opioid agonist. But I think the ortho-chloro group in your version would remove the other two effects.

If only i had my own lab, i probably would have already synthed and tasted some of these.

 

[wungchow]

i think even simpler variations of lefetamine would yield interesting compounds.

 

[Reminisant B]

^ The cathinone derivative looks an interesting compound.

 

[Ham-milton]

they'd also be more likely to be scheduled as analogues, though. Anyone know if two and three of the original post have been synthed? Look interesting, for sure.

 

[mad_scientist]

mad scientist:

i think adding a hydroxyl group would definitely improve mu-opioid binding but in general -OH groups on the phenyl ring makes the compound into a crap DAT inhibitor.

Yeah thats true. It seems quite difficult to make a compound thats a potent DAT inhibitor and a potent mu agonist, most compounds with both effects are pretty low potency but just happen to bind to both targets well enough to show combined effects in vivo.

How about a p-fluoro then? In the paper J. Med. Chem. 2005, 48, 1336-1343 where they make a bunch of analogues of pethidine (meperidine) with increased stimulant effects, pretty much all of them lose most of their mu-opioid affinity except for the p-fluoro analogue which is a more potent stimulant but still retains around 60% of the mu-opioid binding affinity of the parent compound. Actually the p-methyl looks quite good as well.

Maybe the p-fluoro, N-phenethyl analogue of pethidine would be a good target seeing as the tropane series of DAT inhibitors seem to tolerate a phenethyl group on the nitrogen and still retain potent DAT inhibitory effects.

Lefetamine is quite unique though in showing mu-agonist, DAT inhibitor and NMDA antagonist effects, I think it would be hard to increase potency at all three targets at once, more likely you could increase one effect, but at the expense of the others. Mind you, ketobemidone is a mixed mu-agonist / NMDA antagonist, and is very similar to pethidine, so I would be tempted to look at that family to try and design new triple acting compounds.

 

[haribo1]

Lefetamine was tested as a 'new' treatment for helping people with opiate dependance. Several other things were tried & buprenorphine was chosen.

F&B, adding that phenol grouping makes a lot of sense. Tapentadol is maybe an interesting template to look at. An example of 'just how simple can we make an opiate'. As for the -Cl group. I've noticed that some of the newest fentanyls have a 2-fluoro group (brifentanil,trefentanil) in them. Got to be some reason for their presence. Once again, it's a dual mode of action both mu agonism and (like tramadol, what a surprise) noradrenaline reuptake inhibition.

 

[Adrenochrome]

Is there credence that fencamfamine is a ligand @ opiod receptors?

 

[Ham-milton]

I haribo1 is probably right, something with a little similarity to tapentadol is probably a good idea for a novel MORA + DARI-type drug. I wonder how hard it'd be to get a tapentadol-derivative with dopamine RI instead of NE reuptake inhibition.

I know I'd much prefer to sample something like that.

NARIs can be enjoyable, but it seems like there's always a decent secondary effect before it's much good. Too bad atomoxetine takes so long for much effect.

 

[haribo1]

Wow, and fencamfamines effects can be blocked by naloxone... thanks for pointing that out. Now, a meta phenol grouping should increase opiate binding....

 

[diche]

WOW, this is so out of my league

 

[haribo1]

Fencamfamine

Anyone suspect that an N-methyl version will be more stimulant?

 

[vecktor]

Fencamfamine

Anyone suspect that an N-methyl version will be more stimulant?

no!
its more toxic though.
n-propyl is supposedly where the action is at