Galantamine and other acetylcholinerase Inhibitors

[CrimpJiggler]

An acetylcholinerase inhibitor is a compound that inhibits the enzyme which breaks down acetylcholine and as a result it increases the amount of acetylcholine present in the brain (and body). This is similar to how MAOIs increase the amount of dopamine and serotonin (and others monoamines) in the brain and rest of the body. Anyhow I came across people talking about galantamine and how it induces lucid dreams. I found that fairly interesting and noticed that they always recommend you take choline supplements with it so I assumed its an acetylcholine agonist or something but I read up on it and its an acetylcholinerase inhibitor. Thats why its used to treat Alzheimers. Anyhow I was reading about other acetylcholinerase inhibitors called miotine and neostigmine. Neostigmine is a charged molecule so it can't cross the blood brain barrier but miotine isn't charged and as a result it does cross the BBB. I read that this is why there can be some unwanted side effects associated with miotine. Now I'm left wondering about galantamine. People take galantamine to increase the acetylcholine in their brains which leads to cognitive enhancing and other properties. Acetylcholine is also a major neurotransmitter of the PNS though and is the primary neurotransmitter responsible for the contraction of muscles. Wouldn't taking galantamine lead to unwanted side effects in the PNS or does it only act in the CNS for some reason?

 

[sekio]

Yes, taking galantamine or other centrally active AChE inhibitors does produce perhipheral effects.

 

[CrimpJiggler]

What kinda effects come with having a surplus of ACh in the PNS?

 

[chuck_norris]

Surplus acetylcholine in the periphery produces what are known as "cholinergic" symptoms. My first year pharmacology is a little rusty but I believe these include salivation, pupiliary dilation, slowing of the heart and urinary retention amongst others. Perhaps muscle spasticity mediated by a subtype of acetylcholine receptor (nicotinic/the one you mentioned about muscle contraction). I do believe that these side effects are the purpose of nerve gases, which are essentially potent and high affinity acetylcholinesterase inhibitors, which ultimately kill by paralysis of the diaphragm.

I'm guessing that the side effects of galantamine at therapeutic doses aren't too noticeable though.

Also there are ways to only target the CNS and leave the PNS unaffected. L-dopa, which is given to Parkinson's patients, is converted to dopamine by enzymes in the periphery and CNS. This is good for relieving sypmtoms caused by dopamine deficiency in the brain, but excess dopamine in the periphery activates nausea centres which cause unbearable vomiting in some patients. So they give these patients an enzyme inhibitor that doesn't cross the BBB, preventing excess dopamine in the periphery but not the CNS. I wonder if something similar could be achieved for galantamine by those who wish to use it in higher doses without unwanted peripheral effects?

 

[CrimpJiggler]

Interesting shit. From what I read, serotonin in the periphery causes cardiac problems. To 5-HTP supplement, they should add a 5-HTP decarboxylase inhibitor which doesn't cross the BBB to counteract the problem of 5-HTP getting converted to serotonin before it reaches the CNS.

 

[fastandbulbous]

Acetylcholinersterase inhibition is how the nerve gases (sarin, tabun etc) work, so be very careful using such things

 

[ebola?]

Right. Luckily, the reversible inhibitors in medical use have a larger margin of safety than the irreversible inhibitors found in military applications. Still, this class of compounds is not something to be trifled with.

ebola

 

[CrimpJiggler]

Acetylcholinersterase inhibition is how the nerve gases (sarin, tabun etc) work, so be very careful using such things

Like chuck norris says though, nerve gases will be very potent AChE inhibitors. An analogy is magnesium as an NMDA antagonist. Mg²⁺ is only a partial NMDA antagonist so it doesn't have the extreme effects induced by PCP or DXM. AChE inhibitors will work by binding to either the active site or an allosteric site of the enzyme so in the case of it binding to the active site, it will depend on how strongly it bonds to the enzyme. Obviously something that bonds covalently to the enzyme will cause far greater effects than a compound that is in equilibrium with the complex due to van der waals forces. If it bonds to an allosteric site then I suppose it depends on what kind of structural alteration is causes. For example allosteric regulation by galantamine might just make the enzyme less potent (can't remember the correct word for amount of reactions an enzyme can catalyse per second).

 

[chuck_norris]

I can't vouch for the authenticity of this information, but I found it quite interesting and relevant to the above conversation. Turns out that not only cholinergics (nerve gases) can be used as weapons of war, anticholinergics are useful as well! Anyone who is familiar with above-clinical effects of atropine/scopolamine might recognise these effects;

http://en.wikipedia.org/wiki/3-Quinuclidinyl_benzilate

 

[CrimpJiggler]

Doesn't surprise me at all that anticholinergics make good candidates for incapacitating agents. The idea of using nerve gas as a remedy sounds pretty crazy but after ingesting a significant dose of anticholinergics, I reckon you'd need a full on AChE inhibitor to counteract the effects.

 

[Gannicus]

Like chuck norris says though, nerve gases will be very potent AChE inhibitors. An analogy is magnesium as an NMDA antagonist. Mg²⁺ is only a partial NMDA antagonist so it doesn't have the extreme effects induced by PCP or DXM. AChE inhibitors will work by binding to either the active site or an allosteric site of the enzyme so in the case of it binding to the active site, it will depend on how strongly it bonds to the enzyme. Obviously something that bonds covalently to the enzyme will cause far greater effects than a compound that is in equilibrium with the complex due to van der waals forces. If it bonds to an allosteric site then I suppose it depends on what kind of structural alteration is causes. For example allosteric regulation by galantamine might just make the enzyme less potent (can't remember the correct word for amount of reactions an enzyme can catalyse per second).

You mean something that will inhibit the substrate concentration, non competitively.

like HIV medication?