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Dihexa: "it would take 10 million times as much BDNF to get as much new synapse formation as Dihexa."


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#1 moomoo

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Posted 12 October 2012 - 11:54 AM


"Harding, Wright, and their colleagues found Dihexa to be seven orders of magnitude more powerful than BDNF, which has yet to be effectively developed for therapeutic use. In other words, it would take 10 million times as much BDNF to get as much new synapse formation as Dihexa."

http://www.scienceda...21011090653.htm



Seems to be a derivative of an angiotensin.

Seems interesting. Who knows what the side-effects are, but for that level of synapse formation I think there may be some people willing to be guinea-pigs. Does anyone know anything about this?

Edited by moomoo, 12 October 2012 - 11:55 AM.

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#2 zeroskater6979

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Posted 12 October 2012 - 12:55 PM

I definitely have some broken synapses that need repairin'
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#3 neuropill

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Posted 13 October 2012 - 09:00 AM

It's protein fragment and I'm looking forward to more research.
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#4 InfaredLighter

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Posted 14 October 2012 - 12:35 AM

Here is a report I found on it: http://jpet.aspetjou...112.199497.long
Seems interesting, and like a fairly simple molecule.
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#5 moomoo

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Posted 14 October 2012 - 03:06 PM

Here is a report I found on it: http://jpet.aspetjou...112.199497.long
Seems interesting, and like a fairly simple molecule.


Furthermore, both studies indicated a clear dose-response relationship between the dose of dihexa and water maze performance



Good find. I've often wished there was a development interesting enough to really experiment with getting some made up by a reputable company, and this seems like one of those chemicals.

Edited by moomoo, 14 October 2012 - 03:44 PM.

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#6 Marios Kyriazis

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Posted 14 October 2012 - 04:26 PM

An interesting development would be to use it in association with BDNF, the result would be much more effective with a reduced risk of side effects.
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#7 OpenStrife

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Posted 14 October 2012 - 09:58 PM

Whoa What? This title seems to imply - or at least it suggests that at such a rate, any thought that comes into your head is permanently linked in your synapse.

I mean comon....
10 million times as much BDNF...


Talk about an absurdly unbelievable claim.
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#8 OpenStrife

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Posted 14 October 2012 - 10:03 PM

Did some research, sounds unbelievably amazing. I would love to get my hands on some of this to try it out.
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#9 zorba990

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Posted 14 October 2012 - 11:46 PM

If you post the amino sequence it would be pretty easy to get some quotes on having it synthesized.
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#10 evo

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Posted 15 October 2012 - 01:19 AM

The third molecule is also a peptidomimetic but, unlike Norleual and PNB-0405, exhibits agonist activity. Labeled Dihexa, this molecule consists of a hexanoic acid in place of the first residue and a 6-amino-hexamide moiety in place of the 3 c-terminal residues (Table 1). The
11
resulting structure is hexanoic acid-Tyr-Ile-(6)amino-hexamide. Dihexa has exhibited promising activity as a potential cognition-enhancing agent in ex-vivo long-term potentiation studies and in behavioral studies using the Morris water maze task of spatial learning (unpublished data).
Table 1. Structure of Angiotensin IV Analogs. Name Structure Angiotensin IV Val-Tyr-Ile-His-Pro-Phe Norleual Nle-Tyr-Leu-(ψ)(CH 2 NH 2 )-His-Pro-Phe PNB-0405 d-Nle-Tyr-Ile-(6)aminohexamide Dihexa Hexanoic-Tyr-Ile-(6)aminohexamide

→ source (external link)


Any comment on potential side effects? Given that the pathway has implications on vascular fluid concentrations it would be good to know of any complications with similar analogues. Curious to find out about synthesis costs...

[edit] Also found this presentation. Check page 17 for more details about chemical structure (PNB-0408) as well as other interesting info[/font]

characterization of angiotensin IV analogs with therapeutic potential for cancer and dementia.

→ source (external link)


Further edit--the forum appears to have issues with references right now and the links will not post correctly. If the reference links aren't working:

1) http://udini.proquest.com/view/pharmacokinetic-characterization-of-goid:753538986/
2) http://www.slideshare.net/alenemccoy/proposal-seminar

Edited by lmlj, 15 October 2012 - 01:29 AM.

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#11 Xenix

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Posted 10 February 2013 - 01:16 PM

I need to get my hands on some of this stuff O.O
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#12 nootlyinclinded

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Posted 11 February 2013 - 06:08 PM

This drug seems extremely interesting. I became somewhat interested in the dosing range and found that about 10-20mg/kg were used in studies on rats. Seems like a rather small amount seeing as studies tend to use over the top dosages anyways. Seeing as such a small amount would be needed, I'm wondering how much custom synthesization would cost.
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#13 Megatrone

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Posted 11 February 2013 - 08:52 PM

I just hope a zillion years haven't passed when we get more news on this compound.
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#14 nootlyinclinded

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Posted 12 February 2013 - 11:44 AM

I doubt I can wait. Does anyone know any company that would possibly be willing to synthesize this compound for an individual?
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#15 Xenix

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Posted 13 February 2013 - 12:22 PM

Dihexa sounds too good to be true; surely it is the God-among-insects of all nootropics... How do you guys think it would affect normal people? Surely it would push the boundary between people seeking treatment for mental disorder/decline and ordinary people searching for cognitive enhancement? but hey, I guess this is what this forum's all about :P
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#16 Divien

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Posted 13 February 2013 - 03:11 PM

I'm currently requesting price quotations for the lulz. Seems it is active in picomolar concentrations, wonder how someone is supposed to weigh this.
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#17 Godof Smallthings

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Posted 14 February 2013 - 09:34 AM

Really? Picogrammole as in one trillionth of a gram mole (edited) - not even a nanoscale would be sufficient, then?

Edited by Godof Smallthings, 14 February 2013 - 09:36 AM.

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#18 obliviron

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Posted 14 February 2013 - 01:56 PM

I'm currently requesting price quotations for the lulz. Seems it is active in picomolar concentrations, wonder how someone is supposed to weigh this.

Any response yet?
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#19 Divien

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Posted 14 February 2013 - 06:09 PM

Yeah, I just got a response. I asked for a fairly large amount considering the active dose. I asked for the price for 1 gram, >98% purity. The response was 970 EUR, from an european service (located in Denmark).



The price includes: Delivery with UPS or TNT Express, certificate of analysis, MS certificate and HPLC certificate.

Delivery time: Approximately 4-5 weeks

This is not the true price, as I forgot to request the price as an acetate salt (extra charge) instead of a trifluoroacetate salt (wouldn't really want to ingest TFA). I don't think it'd change it very much though.
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#20 nootlyinclinded

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Posted 14 February 2013 - 07:31 PM

Hmm, keep me updated, I would be willing to drop some money on it with you so long as we can work some sort of system out in which I don't get screwed. Btw, have you inquired on any other company to see if you can get cheaper rates elsewhere?
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#21 Divien

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Posted 14 February 2013 - 08:29 PM

I haven't checked with other companies but I requested another price quotation from the same place. 100mg, purity >98%, acetate salt. Should be more than enough to gauge the effects. Where are you located? EU? US? Other? Have you got any system in mind?
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#22 Rior

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Posted 14 February 2013 - 08:52 PM

I have some very unfortunate news for you all. I was hesitant about posting this, as it's potentially libel, however it's the truth coming from the horse's mouth so-to-speak. I want to make it very clear: my following statement is by NO MEANS my way of saying that the aforementioned product (Dihexa) ABSOLUTELY CAUSES said effects I am about to list, I am merely theorizing. It is up to further testing to confirm whether or not the following statement will be an issue.

Anyway. That said, I spoke with the CEO of M3 Biotechnology (manufacturer of Dihexa) over email about a month or two back. I inquired as to the direct mechanism of action, how it worked, etc etc, as I was curious if it was simply some kind of positive allosteric modulator of the TrkB receptor, or something else. I will not copy and paste the emails, however I will paraphrase to give the general gist:

It was stated to me that Dihexa is a "small molecule agonist of HGF (hepatocyte growth factor)" HGF is the obligate ligand of the c-Met receptor, a tyrosine kinase receptor similar to TrkB, and a receptor that Angiotensin IV seems implicated in activating. To quote part of the email, "c-Met is localized in dendrites and HGF activation seems to result in synaptogenesis, neuritegenesis and neurogenesis."

Now this all sounds fine and dandy, great potential there. However, this part scares me: quoting WIKIPEDIA, (not always the most pure of authors):

Abnormal MET activation in cancer correlates with poor prognosis, where aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis) that supply the tumor with nutrients, and cancer spread to other organs (metastasis). MET is deregulated in many types of human malignancies, including cancers of kidney, liver, stomach, breast, and brain. Normally, only stem cells and progenitor cellsexpress MET, which allows these cells to grow invasively in order to generate new tissues in an embryo or regenerate damaged tissues in an adult. However, cancer stem cells are thought to hijack the ability of normal stem cells to express MET, and thus become the cause of cancer persistence and spread to other sites in the body.



And here is where the problem in my mind lies. I am by no means saying that Dihexa absolutely has the potential to cause cancerous growth, all I am saying is that it seems that overactivation of the c-Met receptor is implicated in the sustenance and growth of tumors. This of course, is why I'm waiting to see what comes from their tests. The person I talked to said that their tests have all come out incredibly well, and their tests have shown drastic cognitive improvement in scopolamine-induced mice alzheimer's dementia model. We just need to see the tests that come after it's been tested on thousands of rats, to see the result. Side-note: they are also reportedly preparing for IND enabling studies, so we'll see this tested on human subjects sometime soon.

That said, I would ABSOLUTELY NOT recommend testing this one on yourself until more test results come out.

Lastly worth mentioning, I made the mistake of mentioning the c-Met issue in my followup email, and after that never got any more responses. For obvious reasons.

Edited by Rior, 14 February 2013 - 08:54 PM.

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#23 mait

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Posted 14 February 2013 - 08:52 PM

Count me in for this experiment!
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#24 medievil

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Posted 15 February 2013 - 12:57 AM

By what pathway does it promote cancer? simply inhibit the next step.
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#25 nootlyinclinded

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Posted 15 February 2013 - 08:50 AM

Thank you for posting that Rior; however, it seems from what is posted, this would only be an issue if an individual already had cancer or some sort of tumor. However, what would exactly happen in an otherwise healthy individual?
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#26 nootlyinclinded

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Posted 15 February 2013 - 09:07 AM

I haven't checked with other companies but I requested another price quotation from the same place. 100mg, purity >98%, acetate salt. Should be more than enough to gauge the effects. Where are you located? EU? US? Other? Have you got any system in mind?

I was thinking I'd paypal you half the money so that you can send it with tracking information, then once I receive it, give you the other half. I am located in the US btw. Also, with Paypal, I believe you can upload the tracking information on paypal; thus in the event that you do not ship it, I can merely file a dispute to garnish back my money.

Edited by nootlyinclinded, 15 February 2013 - 09:08 AM.

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#27 Xenix

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Posted 15 February 2013 - 02:48 PM

Well, the way I see it is that my brain is already fried, so I might as well get a few years of decent cognitive function out of it than a lifetime of blah. Heh, maybe I'd even discover the cure to the potential brain cancer I'd induce on myself with the cognitive gains I'd develop from the Dihexa.

Count me in for this experiment!


Me too.
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#28 Xenix

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Posted 15 February 2013 - 02:53 PM

I haven't checked with other companies but I requested another price quotation from the same place. 100mg, purity >98%, acetate salt. Should be more than enough to gauge the effects. Where are you located? EU? US? Other? Have you got any system in mind?


100mg?! amazing!!! Please let me know how this goes, I would be EXTREMELY keen on obtaining Dihexa in this quantity.
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#29 Rior

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Posted 15 February 2013 - 06:17 PM

By what pathway does it promote cancer? simply inhibit the next step.


aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis) that supply the tumor with nutrients, and cancer spread to other organs (metastasis).


Right there, unfortunately. If Dihexa is a positive allosteric modulator of the c-Met receptor, I would certainly think that would qualify as causing "aberrantly active c-Met activation." Granted, I certainly home I'm wrong and feel that it may be likely that I am considering they're about to start IND tests, however I feel this c-M et overactivation is certainly something worth bringing up for discussion.
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#30 mait

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Posted 15 February 2013 - 07:37 PM


By what pathway does it promote cancer? simply inhibit the next step.


aberrantly active MET triggers tumor growth, formation of new blood vessels (angiogenesis) that supply the tumor with nutrients, and cancer spread to other organs (metastasis).


Right there, unfortunately. If Dihexa is a positive allosteric modulator of the c-Met receptor, I would certainly think that would qualify as causing "aberrantly active c-Met activation." Granted, I certainly home I'm wrong and feel that it may be likely that I am considering they're about to start IND tests, however I feel this c-M et overactivation is certainly something worth bringing up for discussion.


As far as my knowledge goes Dihexa is a AT4 receptor antagonist. And if we look the evidence outlined in from previously linked slide-presentation if anything the compound inhibits cancer growth. And I do not believe that rebound effects of angiotensine levels after cessation of Dihexa treatment would be a big problem because angiotensine IV is itself at the end of angiotensin metabolism pathway.

I think the bigger problem in terms of cancer risk is increasing Your angiotensine II levels by taking usual AT-1 receptor antagonists (for example losartan) - this would increase the angiotensine II levels that would also increase the levels of it's metabolites angiotensine III and IV therefor increasing cancer risk via angiotensin IV signaling.

I did some quick googleing and found even some evidence for the mechanism I described above.

Edited by mait, 15 February 2013 - 07:39 PM.

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