Tezampanel

[Jamshyd]

Tezampanel (LY-293,558) is a drug originally developed by Eli Lilly[1] which acts as an antagonist at the AMPA and kainate families of ionotropic glutamate receptors,[2][3] with selectivity for the GluR5 subtype of the kainate receptor.[4][5] It has neuroprotective[6] and anticonvulsant[7] effects. The neuroprotective actions may, at least in part, occur by blocking calcium uptake into neurons.[8]

Tezampanel has a range of effects which may be useful for medicinal purposes, as well as its applications in scientific research. It suppresses both the withdrawal symptoms from morphine and other opioids,[9][10][11] and the development of tolerance,[12] as well as having antihyperalgesic[13] and analgesic effects in its own right.[14][15][16][17][18] It also has anxiolytic effects in animal studies and has been suggested as a candidate for the treatment of anxiety in humans.[19]

(Bolding/underlining mine)

Somehow, I feel this drug might be a godsend. I'd give an arm and a leg to accquire some and try it.

To clarify: I mean a godsend as medicine, not as a buzz.

 

[dread]

It suppresses both the withdrawal symptoms from morphine and other opioids,[9][10][11] and the development of tolerance,[12] as well as having antihyperalgesic[13] and analgesic effects in its own right

Wow. Gotta get me some of that...

 

[fryingsquirrel]

Yeah that's what I was thinking. Any ideas on how? I mean is this a presciption drug one could get from an online pill-mill or is it more exotic? Something tells me I won't find an RC vendor stocking this.

 

[Jamshyd]

As far as I know, it seems to only exist in the catalogues of Sigma-Aldrich or Tocris or that sorta thing.

I *really* doubt you'll find this sold as an RC. It doesn't strike me as anything that would get you high. It would be difficult to market to the meph generation .

But it really seems to combine the best of the medical effects of Ketamine and Gabapentin and, as anyone who follows ADD regularly knows, I keep touting these two drugs as snake-oil . I guess all I can do is hope it gets approved as a prescription drug.

 

[fryingsquirrel]

Maybe not the meph generation but some of junkies in OD would probably pay good money Actually I could see this getting approved as a prescription drug, I'm thinking pharmacuetical companies might be interested in something for opiate addicts they can't get high on. Wonder who owns the patent though.

 

[P A]

Looks like it would have implications for schizophrenia too...

On the other hand, I've watched too many drugs fall from their paper thrones in clinical practice to be horribly impressed by rat studies anymore. Let's wait for some actual trials.

In the meantime I think I'll just stick with my tranquilizers, Zofran, and putrid cough syrup.

 

[seep]

Not meaning to hijack this thread, but does anyone know of data on human use of 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate, shorthand CPP, potent non-competitive NMDA antagonist, saturated and superior form of midafotel, absent from Wikipedia, structural formula

, proven in mice to eliminate diazepam withdrawal and reverse diazepam tolerance?

Search engine leads me to a post of myself asking the same question, but maybe I missed something.

 

[mad_scientist]

Tezampanel may have useful therapeutic effects as you surmise, but being an AMPA antagonist I would expect some rather profound mental dullness and amnesia as common side effects.

Though not directly comparable, mGluR5 receptors have similar functions to AMPA in many respects, and the mGluR5 negative allosteric modulator fenobam never made it to market because of precisely this kind of shortcoming.

 

[Jamshyd]

Tezampanel may have useful therapeutic effects as you surmise, but being an AMPA antagonist I would expect some rather profound mental dullness and amnesia as common side effects.

Why do you think so?

Is this because the so-called "nootropic" piracetam is an AMPA agonist?

If so, I'd be very welcoming to such dullness, as piracetam causes me to get suicidal.

 

[tBirdee]

What's wrong with Ontario!?

I like it here

edit: oh shit I fergot this was ADD sorry for the off-topicness!

 

[P A]

piracetam causes me to get suicidal.

...srs? Piracetam? A cholinergic mechanism maybe?

I don't remember ever reading a study mentioning depression as a common AE...placebo incidence?

 

[Jamshyd]

No study perhaps, but that's understandable as people basically take it for granted that these drugs have absolutely no adverse effects.

However, if you search this forum you'll find several people have had similar experiences.

Piracetam, Oxiracetam, and Nefiracetam all did the exact same thing to me - no effects for 2 days, and on day 3, a sudden and very accute depression that lifts as soon as I stop taking them.

I doubt it has anything to do with a cholinergic effect, as Huperzine-A and plain old Nicotine are just fine with me.

On the other hand, it is basically a well-known fact now that the 'racetam drugs basically block all of the effects of Ketamine, and as Ketamine is the best antidepressant (in small doses) I'd ever tried, I'd say it has more to do with glutamatergic systems.

I also don't know what you mean by "placebo" - for something to be Placebo, you'd have to anticipate its effects. When I took 'racetam drugs, I actually anticipated nothing other than an intellectual boost - which didn't happen.

 

[P A]

for something to be Placebo, you'd have to anticipate its effects

Not necessarily. I've heard of/witnessed some pretty fucking bizarre psychoactive drug effects not at all expected [and in many cases contrary to expectation], nor soluble through mechanistic rationalizations. I usually chalk this up to the so-called 'placebo effect,' though I'm not sure if the two phenomena are truly separate entities.

I'd say it has more to do with glutamatergic systems.

Or downstream consequences thereof. Site-specific NMDA-Glycine agonism on cortical cholinergic neurons would more-or-less selectively (indirectly) agonize postsynaptic muscarinic receptors, the selective blockade of which also quickly resolves depressive anergy in a similar manner as ketamine and the other NMDA channel blockers. Ketamine's dopaminergic properties aside, I'd actually be willing to bet it's a common mechanism.

Or am I an idiot? Now that you remind me, I don't know as much about the NMDA dissociatives' relevance to non-schizoid psychiatric syndromes as I should, and you obviously have quite a bit of interest. Care to link a thread explaining ketamine's antidepressant mechanism(s) plox?

 

[KAYLA2010]

The blocking effects of calcium reuptake, by this med, helps with tolerance?

I am pretty sure it does....and i feel dumb for asking but someone please assure me or not..........

 

[seep]

In Bethesda the NIMH has been spiking acutely depressed subjects with Ketamine for nearly a decade but the mechanism seems dependent on AMPA throughput, not antagonism:

NSFW:

1. Biol Psychiatry. 2008 Feb 15;63(4):349-52. Epub 2007 Jul 23.

Cellular mechanisms underlying the antidepressant effects of ketamine: role of
alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.

Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK.

Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and
Anxiety Disorders Program, National Institute of Mental Health, National
Institutes of Health, Department of Health & Human Services, Bethesda, MD 20892,
USA.

Comment in:
Biol Psychiatry. 2008 Feb 15;63(4):347-8.

BACKGROUND: Ketamine exerts a robust, rapid, and relatively sustained
antidepressant effect in patients with major depression. Understanding the
mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA)
antagonists could lead to novel treatments with a rapid onset of action. METHODS:
The learned helplessness, forced swim, and passive avoidance tests were used to
investigate ketamine's behavioral effects in mice. Additional biochemical and
behavioral experiments were undertaken to determine whether the
antidepressant-like properties of ketamine and other NMDA antagonists involve
alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor
throughput. RESULTS: Subanesthetic doses of ketamine treatment caused acute and
sustained antidepressant-like effects. At these doses, ketamine did not impair
fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective
antagonist, also exerted antidepressant-like effects; these effects, however,
were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA
receptor antagonist, attenuated both ketamine-induced antidepressant-like
behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors.
CONCLUSIONS: NMDA antagonists might exert rapid antidepressant-like effects by
enhancing AMPA relative to NMDA throughput in critical neuronal circuits.

PMID: 17643398 [PubMed - indexed for MEDLINE]

and many more sources corroborate. A Pubmed Central search of MAENG KETAMINE will lead to 23 free full-text articles, at least 5 of which are worth reading. This is all kind of vogueish post-monoamine era psychopharmacology and is very poorly understood at the moment.

Interesting thread this one.

 

[fastandbulbous]

Easily the most convoluted amino acid structures I've seen, even weirder than some of the ones found in fungal toxins!

 

[negrogesic]

Though convoluted the synthesis is far from impossible; may you can request a custom synth....

 

[Ximot]

@Jamshyd: ever managed to find this? since it works on glutamate receptors it might do "the K trick" for me... as i stopped using K...

I am similar to you in my dysphoric tendencies though it seems mine are interspersed with periods of hypomania. Sadly I am also prone to abusing the drugs that help me the most. Thus i went through 30 grams of ketamine in a few months, bumping pretty much daily, as needed, and more, for fun, till I realised life was utter terror without it. I used it as a reality buffer really. Too bad. Enter gabapentin, new godsend... but again I found myself using it a LOT and going a bit out of control on it, not least behaviourally, and ending up feeling crap without it later... tianeptine, which you'd mentioned before, is another drug that works well in mysterious ways... though more alert after taking it I feel as if i could even sleep on it, that calm am i at the same time. None of the stim tension that even modafinil will give me at high doses... so yeah, for all those reasons, tezampanel intrigues me...

 

[MagickalKat777]

Looks like the replacement Dope-a-Max... fuck that. Topiramate is nasty shit. I, too, share the concerns about the dope (as in idiot) factor.

 

[wungchow]

We all know how well animal studies correlate to actual human responses to the drug...

I wouldn't hold my breath - there have been so many claims of "tolerance-reducing" drugs/supplements which mostly seem to have no effect...