N&PD Moderators: Skorpio
1,2-dihydro-1,2-azaborine and other heterocyclic C65xH6 ring psychedelics/stimulants?
Limpet_Chicken
Bluelighter
Does anybody have any idea whether analogs of known psychedelic phenethylamine/amphetamines where the phenyl ring is replaced by a 1,2-dihydro-1,2-azaborine ring would be active? or perhaps other heterocyclic rings such as pyridine, phosphazine etc?
belligerent drunk
Bluelight Crew
Not sure about activity, but I suspect a pyridine ring would greatly increase toxicity.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974919/
This paper says that 1,2-dihydro-1,2-azaborine is highly susceptible to oxidation by the CYP450 family of enzymes (and probably others, too) so their usefulness as pharmaceuticals (or recreational drugs, for that matter) might be limited.
bindingaffinity
Bluelighter
Unless you administered them parenterally, right? (Of course that would only get you past liver enzymes... if enzymes in the brain also oxidize it then no dice.)
Good luck finding a bioisostere for phenethylamines, this seems like a very interesting and worthwhile path even if 1,2-dihydro-1,2-azaborine itself doesn't pan out.
There's thiopropamine (amphetamine with a thiophene ring replacing benzene). Add a couple methoxy groups at positions 3 and 5, something hydrophobic at 4, and maybe you'd get something interesting, but almost certainly worse (qualitatively and in potency) than the corresponding amphetamine, and not remotely worth the synthetic effort.
A pyridine ring would probably give you something histaminergic.
The pyrovalerone homologue has been studied and found to be as disappointing as the simple methamphetamine homologue compared to it's parent. A couple of papers on it are listed by Reaxys but nothing of value. I'm sure the Chinese RC vendors would have thrown them out if they were of commercial value to people selling untested compounds with the implicit reason of consuming them.
Limpet_Chicken
Bluelighter
Methiopropamine? have tried it, and quite honestly, couldn't tell much of a difference between it and meth.
Here's a thought..borazine is stable enough to be prepared (IIRC from diborane and NH3...not exactly the most appetizing prospect, given the nature of diborane. Never had the...'opportunity' of dealing with B2H6, although have with pentaborane, and none of the family are particularly pleasant, AFAIK, but have dealt with worse), and its isoelectronic and isosteric with C6H6; would the phosphorus homolog be sufficiently stable for such purposes?
sekio
Bluelight Crew
Don't trust wiki too much, borazine is not isoelectronic with benzene, despite having same number of electron.
The distribution of them is very different.
Also, borazine hydrolyses in water.
belligerent drunk
Bluelight Crew
^ yeah, due to the differences in electronegativity, the bonding is different from the perfectly aromatic one is benzene. Also affects bond angles.
@Limpet: phosphorus analogues are lousy at forming aromatic rings. AFAIK its atomic radius is too large to form stable sp2 hybridized orbitals necessary for aromatic rings.
Limpet_Chicken
Bluelighter
Do substituted derivatives also hydrolyze?
Yes, with slower rate but still too significant to be stable in "aqueous environment" like the body. (60-70% )
I don't store borazine(s) in solution with more than 1% of water or it degrade too much
I think it must say something that while Si has made it to candidates, it's never ended up in a licensed medicine. Derek Lowe has written a lot of commentary on it which is well worth the read. Well, in truth I think 'In The Pipeline' should be read by all.