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Huperzine A and NMDAr antagonism and NGF-secretagoge activity


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#1 Lestat Rett

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Posted 22 April 2010 - 10:34 PM


What is the nature of huperzine-A concerning its effects on the NMDA receptor?

What is known of subunit-selectivity at NMDArs, affinity, efficacy etc?
Also is the blockade of NMDArs voltage dependent, or is it a simple channel blocker at the PCP site? obviously its not strong enough to cause dissociative effects if it is indeed a PCP site antagonist, or if it is, then it would cause cholinergic toxicity at doses way below those dissociative effects appear.

I'm currently having a lot of success with huperzine-A at between 600-800mcg/d but I'm wondering what effects its NMDA antagonism might have on memory, and if piracetam or an ampakine would synergise particularly well with it.

Also, wikipedia lists it as an NGF releaser, anybody have more info on that? as huperzine A is almost always referred to as a simple AChE inhibitor.

#2 haha

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Posted 23 April 2010 - 12:55 AM

Im glad to hear that your having success with Huperzine A, Huperzine a maybe a fragment of an endongenous sigma-1 molecule. To bind to sigma-1 takes three domains, with a nitrogen in a hydrophilic centre domain. Huperzine looks like one domain(usually a phenyl or piperazine).


I have tried Donepezil which effects ACHeI through agonistic effect at sigma-1, sigma1 potentiates the NR1a pore of the nmda receptor this doesnt alow Ca2+ entry so is almost like ampakine, but it inhibits the NR2(x)'s which are the functional Ca2+ pores mainly(so this would be the antagonisum).Donepezil is a potent NGF aswel. I found this drug really did improve intelligence but id start to feel more and more depressed as the days went on, maybe antagonist D4.It also wasnt good for my heart or lungs. It may cause excitoxicity to, like once you start you cant stop. Donepezil is in the functional state of binding so the body has no power to rate limit its production which it would have with huperzine a assuming it were to be a sigma-1.

Pharmacology and therapeutic potential of sigma(1) receptor ligands, this is a really good article but i cant get for free atm

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#3 LabRat84

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Posted 23 April 2010 - 03:16 AM

Pharmacology and therapeutic potential of sigma(1) receptor ligands, this is a really good article but i cant get for free atm


Yes you can: http://www.ncbi.nlm....84/?tool=pubmed
Maybe if you're outside the US it doesn't work? Try using a US-based proxy.

#4 KimberCT

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Posted 24 April 2010 - 04:54 PM

Here's the PDF for anyone who can't access it.

Attached Files



#5 chrono

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Posted 24 April 2010 - 06:49 PM

A few tidbits concerning Hup A/NMDA:

11920920: "These results suggest that HUP-A might interfere with and be beneficial for excitatory amino acid overstimulation, such as seen in ischemia, where persistent elevation of internal calcium levels by activation of the N-methyl-D-aspartate (NMDA) glutamate subtype receptor is found...Therefore, HUP-A most likely attenuates excitatory amino acid toxicity by blocking the NMDA ion channel and subsequent Ca2+ mobilization at or near the PCP and MK-801 ligand sites...By blocking NMDA ion channels without psychotomimetic side-effects, HUP-A may protect against diverse neurodegenerative states observed during ischemia or Alzheimer's disease."

11516831: "Huperzine A reversibly inhibited the NMDA-induced current (IC(50)=126 microM, Hill coefficient=0.92), whereas it had no effect on the current induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate or kainate. The effect was non-competitive, and showed neither 'voltage-dependency', nor 'use-dependency'... From these we suggest that huperzine A acts as a non-competitive antagonist of the NMDA receptors, via a competitive interaction with one of the polyamine binding sites."

10437121: "Hup A reversibly inhibited NMDA-induced current in a concentration-dependent manner with IC50 of 45.4 mumol.L-1."

And lots of neuroprotection! Back when I was first looking into choline here, I remember reading some vague warnings about not inhibiting AChE if you're young. But I'm seriously rethinking this now (will at least look into it more thoroughly):

15956816: "HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53 and caspase-3, protect mitochondria, and interfere with APP metabolism. Antagonizing effects on NMDA receptors and potassium currents may contribute to the neuroprotection as well."

I was unable to find any connection between Hup A and sigma receptors, except the mention in this thread.
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#6 haha

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Posted 25 April 2010 - 02:03 AM

Polyamine are sigma's, a doc confirmed, if you look at the effects and compare them with protypical sigma-1 agonist you will find them to be the same. I couldnt really find much info on the net regarding the sigma-1 affinity of any drug on the market.

#7 chrono

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Posted 25 April 2010 - 02:54 AM

Have you seen what the moledules Hup A and donepezil look like? You can't guess at receptor binding based on a few similar functional groups in drastically different configurations. That is in NO WAY how structure-activity relationship works.

There is information about which drugs bind to which sigma receptors all over the internet (including this paper that's been posted in two threads). There's nothing for Hup A because it doesn't bind to sigma-1. If I'm wrong, find me a paper. Not hearsay.

#8 haha

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Posted 25 April 2010 - 07:05 AM

Have you seen what the moledules Hup A and donepezil look like? You can't guess at receptor binding based on a few similar functional groups in drastically different configurations. That is in NO WAY how structure-activity relationship works.

There is information about which drugs bind to which sigma receptors all over the internet (including this paper that's been posted in two threads). There's nothing for Hup A because it doesn't bind to sigma-1. If I'm wrong, find me a paper. Not hearsay.


Good points I will do my best, I have seen what they look like donepezil is a protypical sigma-1 agonist mainly because 3,4dimethyloxyphenyl, sigma-2 requires only one methyl oxy to be present.
The polyamine site on the NMDA recetpor represents an insertion of the adaptins sigma and maybe all the opoid aswell.THis quote maybe shows some indication.

The data indicated that a considerable degree of structural variation is possible while still retaining nanomolar affinity at sigma receptors. As the structure of the polyamines was varied, their binding at sigma-1 and sigma-2 subtypes showed quite different and in some cases opposite trends, supporting the belief that these are pharmacologically distinct entities. Polyamines containing two nitrogen atoms showed optimal binding at both sigma-1 and sigma-2 receptor subtypes sources from"A new approach to the design of sigma-2-selective ligands: synthesis and evaluation of N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1- pyrrolidinyl)ethylamine-related polyamines at sigma-1 and sigma-2 receptor subtypes."

Then from your post "From these we suggest that huperzine A acts as a non-competitive antagonist of the NMDA receptors, via a competitive interaction with one of the polyamine binding sites"

The cholinergic system, sigma-1 receptors and cognition.
Abstract
This article provides an overview of present knowledge regarding the relationship between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. Sigma-1 receptors, initially considered as a subtype of the opioid family, are unique ligand-regulated molecular chaperones in the endoplasmatic reticulum playing a modulatory role in intracellular calcium signaling and in the activity of several neurotransmitter systems, particularly the cholinergic and glutamatergic pathways. Several central nervous system (CNS) drugs show high to moderate affinities for sigma-1 receptors, including acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol, rimcazole)(ANTAGONIST), selective serotonin reuptake inhibitors (fluvoxamine, sertraline) and monoamine oxidase inhibitors (clorgyline). These compounds can influence cognitive functions both via their primary targets and by activating sigma-1 receptors in the CNS. Sigma-1 agonists show powerful anti-amnesic and neuroprotective effects in a large variety of animal models of cognitive dysfunction involving, among others (i) pharmacologic target blockade (with muscarinic or NMDA receptor antagonists or p-chloroamphetamine); (ii) selective lesioning of cholinergic neurons; (iii) CNS administration of beta-amyloid peptides; (iv) aging-induced memory loss, both in normal and senescent-accelerated rodents; (v) neurodegeneration induced by toxic compounds (CO, trimethyltin, cocaine), and (vi) prenatal restraint stress.

SA4503 elicited the increase in extracellular acetylcholine level in rat frontal cortex, while it did not affect the striatal acetylcholine level. On the other hand, tetrahydroaminoacridine (THA), an acetylcholinesterase (AChE) inhibitor, increased the extracellular acetylcholine level in both regions. Although both compounds had anti-amnesic effect against scopolamine-induced memory impairment, THA also induced catalepsy in rats(ACETYLCHOLING IN THE STRATIUM CAUSE SOLELY THETA WAVES,WHICH ARE INCOMPATABLE WITH MOVEMENT)

Interaction with sigma(1) protein, but not N-methyl-D-aspartate receptor, is involved in the pharmacological activity of donepezil(SIGMA 1 ANTAGONTISUM OF NMDA I THINK IS TIME DEPENDENT, TAKES 6 HOURS TO TAKE EFFECT).

I have obviously comeup with very little hard evidence, but have highlighted information that points to me being correct

Edited by haha, 25 April 2010 - 07:07 AM.

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#9 chrono

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Posted 25 April 2010 - 07:22 AM

Thanks haha, it's really appreciated that you're taking time to explain your ideas. It's possible that you're correct, as I haven't seen anything specifically stating Hup A isn't sigma-binding. But I think if it was that obvious from the structure that it binds to sigma, someone would have included it in one of the simple agonist/antagonist studies by now. Beyond the structural commonality, I think the similarities are pretty circumstantial. They do have a confirmed crystal structure of how it binds to AChE, so sigma isn't needed to explain its action.

#10 haha

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Posted 25 April 2010 - 08:25 AM

THey do for Donepezil aswell, sigma-1 maybe complexed in that ache. sigma can be regarded as an activating factor, maybe its just its involvment with the vescular transport of ACH, not to sure. Or maybe the NMDA effects cause ACHE inihibtion as a down stream consequence and they have fudged the binding study

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#11 LabRat84

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Posted 25 April 2010 - 08:55 AM

The PDSP Database - for all your receptor binding affinity needs. (Well, most, anyway.)




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