ZY-1 (nicotine analog)

[Smyth2]

I found this online recently while search an Alzheimer's journal and thought I wanted to share it. The patent (see pubchem) also has the pyridine nitrogen in the reverse location but this is not ZY-1 though.

Froestl, W., Muhs, A., Pfeifer, A. (25 July 2014). "Cognitive Enhancers (Nootropics). Part 1: Drugs interacting with Receptors. Update 2014". Journal of Alzheimer’s Disease. 41 (4): 961–1019. doi:10.3233/JAD-140228.
Nie H, Wang Z, Zhao W, Lu J, Zhang C, Lok K, Wang Y, Shen H, Xu Z, Yin M. New nicotinic analogue ZY-1 enhances cognitive functions in a transgenic mice model of Alzheimer's disease. Neurosci Lett. 2013 Mar 14;537:29-34. doi: 10.1016/j.neulet.2013.01.001. Epub 2013 Jan 20. PMID: 23340201.
He N, Wang Z, Wang Y, Shen H, Yin M. ZY-1, a novel nicotinic analog, promotes proliferation and migration of adult hippocampal neural stem/progenitor cells. Cell Mol Neurobiol. 2013 Nov;33(8):1149-57. doi: 10.1007/s10571-013-9981-0. Epub 2013 Sep 22. PMID: 24057433; PMCID: PMC11497915.

Also the synthesis is not that difficult but someone said not to post details on this forum. Here is a quick overview though:

 

[TheLightBringer]

Nice find, ill give it a read

 

[4DQSAR]

Any more recent references?

I would ask why that final resolution was undertaken. I think by 2013 evergreening was a recognized methodology so if I see a single stereoisomer, I always wonder why one would go through the pain of performing what I suspect to be a novel resolution so likely quite low yielding.

I mean, I get that for research purposes yield only needs to be 'enough' but it adds complexity to what is already a long synthesis. I GET it's a rigid nicotine analogue but am uncertain what it offers to be worth so much effort. I only know that most nicotinic ligands have a narrow TI which is why those novel analgesics went nowhere... well, we did learn that the ultimate source of poison dart frog toxin was from it's diet although I'm uncertain if we ever isolated the specific insect(s) responsible. So finding that would be interesting.

I would point out that nicotine doesn't have a great TI. Give a non-smoker a cigarette and if they smoke it, chances are they will be subject to nasty side-effects. Give a smoker a Senior Service, Capstan Full Strength or similar unfiltered high-nicotine cigarette and they will likely experience some nasty side-effects. But those strong brands don't contain an order of magnitude more nicotine. As a kid I've seen people who smoked those brands offer a cig to others... to laugh at the unwitting victim puking. Now it's entirely possible to produce tobacco with even more nicotine in it, but nobody smokes the stuff. It was used as a source of nicotine for use as a pesticide. Go into a greehouse while nicotine is being evaporated and it can be fatal.