eEF2K inhibitors as novel rapid-onset antidepressants. NH125, Rottlerin, etc.

[Marauder]

What sparked my interest:
http://healthland.time.com/2011/06/...ub-drug-ketamine-lifts-depression-so-quickly/

More technical: http://www.genengnews.com/gen-news-...eloping-fast-acting-antidepressants/81245309/

If you don't want to read those, here's the gist:

"We know that ketamine can produce a fast-acting antidepressant response in treatment-resistant patients, but no one really knows how that works. What we found is a necessary pathway for ketamine to trigger [that response]," says Monteggia. "We've identified a novel pathway never before linked to any behavior, let alone an antidepressant response — that could be a novel drug target."

That means drugs that inhibit or block eEF2 kinase could potentially work as antidepressants — ones that would take effect faster than any current medication and possibly without the "trippy" side effects that make ketamine desirable to some recreational users. Compounds like this currently exist.

"It sounds very, very exciting," says Emery Brown, professor of computational neuroscience at MIT, who was not associated with the research. "If they're correct, it most certainly could lead to new drug development. This is the first time I've heard of this possible mechanism."

However, none of these compounds are currently on the market for any use and it's not known what other kinds of side effects they might have, Monteggia says.

The implications of the research go beyond possible drugs based on eEF2 kinase. The research shows that ketamine acts on brain circuits that are constantly active "in the background" — cells that are activated not when you do something or have an experience, but that are always sort of humming along, no matter what else you are doing or thinking.

"That background stuff might not just be the background," Monteggia says. "It might be important. The problem in mental illness may be a function of background neurotransmission."

"This is bringing a whole new insight into how we might want to construct these types of drugs," says Brown. "It could make us rethink how we approach this entire problem."


Read more: http://healthland.time.com/2011/06/...ne-lifts-depression-so-quickly/#ixzz1PWQ08CZP

The compounds mentioned are:

Rottlerin

http://www.ncbi.nlm.nih.gov/pubmed/8123051

Inhibition of PKC appears, at least in part, to be due to a competition between rottlerin and ATP. Among the protein kinases tested, only CaM-kinase III is suppressed by rottlerin as effectively as PKC delta. The chemical structure of rottlerin might serve as a basis for the development of novel inhibitors with improved selectivity for a distinct PKC isoenzyme, such as PKC delta, or for CaM-kinase III.

(Imidazole compounds, basics: http://en.wikipedia.org/wiki/Imidazole#Biological_significance_and_applications )

eEF-2 Kinase Inhibitor, NH125

inhibits the activity of bacterial histidine kinases (EnvZ, PhoQ, BvgS, and EvgS) and eukaryotic eEF-2 (elongation factor 2) kinase/CaMKIII (IC50 = 60 nM), while exhibiting much lower potency against PKC, PKA, and CaMKII (IC50 = 7.5, 80, and >100 µM, respectively).

(links all go to commercial labs, so not providing any here)

Other relevant data to look up is MK-801, PCP, methoxetamine, Olney's Lesions:

http://en.wikipedia.org/wiki/Dizocilpine
I found this interesting:

Rats learned to lever-press in order to obtain injections of MK-801 into the nucleus accumbens and frontal cortex, however, when given a dopamine antagonist at the same time, the lever-pressing was not altered, which shows that the rewarding effect of MK-801 is not dependent on dopamine.[33] Intraperitoneal administration of MK-801 also produced an enhancement in self-stimulation responding.[34]

DO NOT attempt ingesting these compounds. I am studying everything mentioned in the technical article above (2nd link.) It would be helpful if others chime in with their own opinions and questions to give all of us greater insight into eEF2K inhibitors, the specific rewarding mechanism not dependent on dopamine, these and similar compounds' potential implications in psychiatry, including psychiatric ketamine administration (or prescription.)

I'm interested in those who've been heavy ketamine users in the past. Do you have any lingering psychological or physiological side effects?

 

[vecktor]

I guess it all depends on how selective are those kinase inhibitors? things could get super complex if they are not selective, rottlerin doesn't appear a very promising lead compound. but then again a lot of crappy unselective kinase inhibitors can be modified well away from the primary pharmacophore to get selectivity, it is just a bit tedious.

there is quite a bit of data out there showing that ketamine users have impaired function on some memory tests IIRC (how ironic I can't remember what the details are, and it has been almost 10 years since I last played with K) so I guess K impairs the ability to remember studies about K.

 

[Marauder]

Yeah they'll have to use the lead compounds to make drugs that are more selective. I'm sure Big Pharma has been on this for awhile now. Getting a drug to the market takes ~8-10 years though.

 

[vecktor]

Yeah they'll have to use the lead compounds to make drugs that are more selective. I'm sure Big Pharma has been on this for awhile now. Getting a drug to the market takes ~8-10 years though.

I think the angle most big pharma appears to have been pursuing is selective and allosteric modulators of NMDAr, so sticking with the NMDA aspect rather than interfering with the downstream mechanism. there was a review not that long ago will see if I can find it.