4-Azapradol (2-diphenylmethyl-piperazine)

[paracelsius]

This is an interesting compound I've come across: 4-aza-desoxypipradol (2-diphenylmethyl-piperazine aka 4-azapradol).

apparently being sold as dopaminergic nootropic stimulant: It is the piperazine analog of desoxypipradol (2-DPMP, 2-diphenylmethyl-piperidine aka Ivory wave) with the piperidine replaced by a piperazine.

It was patented in a old Dutch patent as a CNS stimulant. Can't pull that one out but I am sure I've seen it some years ago (would appreciate a link if anybody came across, thx).

Apparently, it is more potent than 2-DPMP as a NDRI and a cocnaine/MPH-like susbtrate but not AMPH-like inhibitor. Now, 2-DPMP is already one of the most potent NDRI iirc (active starting at 5mg-ish!). That means this compound may be active at micrograms range?!.. One advantage tho it may have shorter half-life than the insane 24h+ of 2-DPMP since the piperazine will decrease the logP by at least 2 log units relaltive to the parent piperidine! making it more polar and more easily excreted. Probably similar DOA to benzylpiperazine BZP (5-7 hours). Lower logP will also make it faster acting compared to highly lipophilic 2-DPMP that tend to accumate in fat and release slowy giving it slower absorption rate, longer half-life and irregular bioavailability. Plus the extra 4-nitrogen may make a nice metabolic handle for conjugation unlike with 2-DPMP or morphodrol (4-oxo-desoxypipradol, morpholine replacing the piperidine)... but I dont know until I try it!

Now, you might wonder why would that one be different from morphodrol which was a bust, had a pretty bad review at least with the nootropics crowd iirc? I don't know. But at least with the DAT transporter it seems a H-bond donor (not acceptor! like with morphodrol Oxygen) increases binding (relative to no H-bond group like in 2-DPMP) and a donor decrease it (like in morphodrol), but I am sure iirc the dutch patent describe it as potent CNS stimulant.. anyway, that is an interesting compound. Now, in that old dutch patent, they make it via pto2 reduction of 2-diphenylmethylpyrazine which itself was made from diphenylacetonitrile and 2-chloropyrazine. Pretty expensive route. Isnt other ways to make it? maybe in 2-step/1-pot from cheap diphenylacetonitrile and piperazine-2-carboxylate??

 

[clubcard]

I looked at this whole series and the morpholine homologue looked interesting, the thiomorpholine more so a)because at the time UK law didn't control it & b)the sulfur can be metabolized thus lowering the T½. If you overlay nomifensine and diclofensine, you will realize just how closely they are related. It would appear that (±)-McN 5652 is currently the ultimate development of the idea.

 

[paracelsius]

^ that's a good idea: the thiomorpholine will surely speed up the metabolism and shorten T1/2. Tho, the sulfoxide(or sulfone) metabolite might be active on its own! how does the thiomorpholine compare to 2-DPMP and morphodrol in terms of time to onset? The reason I am asking for highly potent compounds like 2-DPMP, time to onset seems critical as people in general think it is not working, redose and ended up in psych ward with full-blown psychosis!!!!

Yes, the 2,2-diarylethylamines all overlay with nomifensine, diclofensine and also mazindol homomazindol..etc. In fact, even the simple 2,2-diphenylethylamine(beta-phenyl-PEA) is actually a potent stim (somehow it survives MAOs unlike PEA, at least in rat). Was described by same McNeil ppl behind McN 5652.

McNeil pyrolloisoquilonines seems good idea but that route they used seems complicated. iirc similar compounds, pyrolloindoles were easily made in 2 steps from tryptamines ( i think James Cook made a lots of these natural products). Wouldn't the same route work with pyrolloisoquinoline using diphenethylamine instead of tryptamine? worth to look at

 

[Rectify]

I'd try it.

 

[polymath]

In fact, even the simple 2,2-diphenylethylamine(beta-phenyl-PEA) is actually a potent stim (somehow it survives MAOs unlike PEA, at least in rat). Was described by same McNeil ppl behind McN 5652.

It's also mentioned as a possible NMDA antagonist in this article (not to be confused with the 1,2-diphenylethylamines that are well-known dissociatives):

NMDA receptor affinities of 1,2-diphenylethylamine and 1-(1,2-diphenylethyl)piperidine enantiomers and of related compounds

We resolved 1,2-diphenylethylamine (DPEA) into its (S)- and (R)-enantiomer and used them as precursors for synthesis of (S)- and (R)-1-(1,2-diphenylet…

www.sciencedirect.com

 

[paracelsius]

It's also mentioned as a possible NMDA antagonist in this article (not to be confused with the 1,2-diphenylethylamines that are well-known dissociatives):

NMDA receptor affinities of 1,2-diphenylethylamine and 1-(1,2-diphenylethyl)piperidine enantiomers and of related compounds

We resolved 1,2-diphenylethylamine (DPEA) into its (S)- and (R)-enantiomer and used them as precursors for synthesis of (S)- and (R)-1-(1,2-diphenylet…

www.sciencedirect.com

Oh I see..compound 22? I wouldn't call it "active" at NMDA tho (Ki only 150microM, about 200X less active than the isomeric 1,2-diphenylethylamine(compound 5) Ki 0.7)! But it is a quite potent stimulant (cf compound 17 here:

https://pubmed.ncbi.nlm.nih.gov/6747990/

At 1.5mg/kg in rats, more or less translate to ~0.3mg/kg in humans. That's pretty potent! Surprising it is stable towards MOAs, unlike the parent PEA (T1/2< 5 min!). Somehow the beta-phenyl makes it resistant to MAOs. Would certainly make a nice functional RC stimulant!

thanks for pointing that out : 2,2-diphenylethylamine:

not 1,2-diphenylethylamine:

 

[polymath]

Oh I see..compound 22? I wouldn't call it "active" at NMDA tho (Ki only 150microM, about 200X less active than the isomeric 1,2-diphenylethylamine(compound 5) Ki 0.7)! But it is a quite potent stimulant (cf compound 17 here:

https://pubmed.ncbi.nlm.nih.gov/6747990/

That's an interesting article, but is there any proof that this compound inhibits dopamine reuptake, and isn't just an adrenergic anxiogen? The effectiveness of the compounds in that study was measured just by motor activity.

 

[paracelsius]

^ Not that I know of if you mean specific Ki for monoamines transport inhibition/release. But the test they used (reversal of tetrabenazine-induced ptosis is pretty indicative) of monoamines uptake inhibition and/or release (tetrabenazine depletes MA). No I dont know if anybody measured that specifically. I just noted (cf table data-notes in the paper) they mention overt CNS stimulant for this specific compound.. but they were a thread in here sometime ago on the diphenylethylamines (some of them like beta-diphenylmethamphetamine are actually ...opioid!!!