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basis for new types of stimulants?

T

thesomoan

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According to wikipedia "When the metabolites of nicotine were isolated and their effect on first the animal brain and then the human brain in people with schizophrenia were studied, it was shown that the effects helped with cognitive and negative symptoms of schizophrenia.. Therefore, the nicotinergic agents, as antipsychotics which do not contain nicotine but act on the same receptors in the brain are showing promise as adjunct antipsychotics in early stages of FDA studies on schizophrenia." Since nicotine itself works primarily on the SNS in addition to being a basis for antipsychotics, couldn't it be made more centrally acting by ( without going into any synth discussion) altering the structure to make it more hydrophobic, and work more on dopamine seratonin receptors, thus making a more euphoric, longer lasting nicotine based stimulant?
 
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I'd hardly describe a cigarette high as "euphoric", nor would I describe it as a proper stimulant...

And yeah, I always thought that the subjective effects were based on MAO inhibition, which is also why smoking while under the influence of other drugs is so pleasurable...
 
I would be very interested in nicotine analogs with improved stimulant effects, most of the research in this area has been done with the aim of creating drugs to aid smoking cessation rather than improvements on the subjective effects of nicotine, apparently nicotine is addictive enough.

At higher doses nicotine can be highly euphoric, the problem is right around the dose where it begins to get good all the other nasty hypercholinergic side effects come in to play, nausea, anxiety, diaphoresis etc. I also find centrophenoxine to be pronouncedly euphoric.
 
Nicotine is mainly neurotoxic because it is such a powerful anticollergen (as i understand it) but the neurotoxicity occurs at a much higher dose than the recreational one, however yes, i was referring to an altered structure which increased CNS effects and wondering which part of the molecule were responsible for which reactions. As i understand it the initial euphoric effects, like the first time you smoke are caused by its release of dopamine and seratonin, but this is mild and quickly tolerance building, thus dependence, while the calming effects are the result of MAO inhibition.
 
Wow that is super helpful, could i perhaps get the citation for that article? That seems to imply that a class of nicotonic drugs could definitely be possible albiet a little ways away.
 
Also, does anyone know which parts of the brain contain nicotine receptors, that would seem to give you a clue what kinds of effects could be possible from its derivatives
 
Maybe I'm a hardhead, but whatever dopamine/serotogenic fx it may have are less than negligable IME. You would be very surprised at just how many thing we ingest daily effect dopamine and/or serotonin. I would bet alot of money that those fx have nothing to do with the addictive fx of cigarettes. A long acting high affinity nicotine type drug would be good however for smoking cessation and skizofrenia. Other than that, trying making it more "euphoric" seems like a waste of time and even a bad idea.
 
Nicotine stimulates the nicotinic acetylcholine receptors and from this you get a cascade down to the dopaminergic system via the noradrenergic. Not as direct as say amphetamine, but in the end, receptors of the acetylcholine system sensitive to nicotine eventually lead to the release of dopamine where it lights up the brain's reward system.

The only thing is, using this system as the target for drugs also sees dopamine released in places most people would rather not have it go, like the CTZ, which controls vomiting; nicotine also causes a rise in dopamine levels there, which is why people usually get nauseous after their 1st cigarette.

I think the designation of the receptor that nicotine acts at is something like a3b4
 
wait Zonk i don't understand why the dopamine/serotogenic effect of nicotine derivatives would be absolutely be negligible what limits its ability to stimulate dopamine receptors? while nicotine itself may have weak affinity it does seem probable that there are much stronger stimulants of nicotonic receptors then nicotine itself
 
What I meant when I said waste of time is that the ridiculous amount of time, work, and $ put into trying to discover a stimulant with a nicotine molecule as a base(which may not even b possible)seems totally pointless when there r so many other easier more logical bases for stims out there. Also if it would still retain its same fx as nicotine does I would never ever want to touch it. Unless yer goal is make a more addictive stim to make $ which doesn't really seem very productive anyway. I could b wrong but all those real novel stims out there were probly discovered more by accident than anything else.
 
Nicotine typically increases amounts of neurons being transported..very quicklu. From seratonin to epinephrine and some other transport agents. It also works as a depressant depending on how you administrate the drug..longer puffs = more relaxed feeling i guess.Although...nicotine is a neurotoxic and has a very short half life. Ideally yous want to increase the absorption rate orally. Which typically runs around 35 percent right now and also decrease the absorption rate and lengethening the half life..but to do this you'd probably need an unusual and unhealthy amount of nicotine. You'd probably have more damage than any positive effects considering that nicotine damages nervous tissue, leading to loss of memory in some cases. You'd have to rebuild the whole structure of a nicotine molecule. And you'd still have to worry about nerotoxicity. If you changed the way it was meatbolited...by the means of Hepatic cyp2d6 or something along those lines. But nicotine does alot more than just increase dopamine/seratonin. Thers alot of other factors slinging around that you havent really thought about. Main course of action would increasing the amount of nicotine absorbed by the receptors. When you take nicotine, its moreso a "BURST" of stimuli. You'd need to lower this absorption rate and increase the amount of nicotine over a period of time...risky.

There are stronger stimulants than nicotine without as much neortoxic damage already... and why would you make it hydrophobic? That would lower your yield absorption rate so much because its not water soluable. Nicotine already has a low enough absorption rate orally. Increasing that absorption rate would probably just increase adverse effects such as nicotine poisoning anyways.

nicotine has a short-lived stimulatory-phase and depressant phase, but a way longer inhibitory phase.
 
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^ care to post a reference for nicotine neurotoxicity at normal plasma levels found in heavy smokers.
there is limited evidence nicotine can alter adolescent rat brains but this doesn't correlate very well with human epidemiological data, especially as mentally ill people often self medicate with nicotine and cannabis for that matter screwing up causality.

Several epidemiological studies indicate nicotine has a effect on reducing the incidence of Alzheimers and Parkinsons disease, a cynic would say this is because the smokers died before they could get old age diseases, the studies supposedly corrected for this.

Some of Abbots subtype selective nicotinic agonists derived from their earlier work on epibatidine have abuse potential with what appears to be a larger 'therapeutic' margin than nicotine itself.

V
 
There are some quantenary nitrogen compounds that act similar to nicotine-stimulation

And this is what I mentt about neurotoxicity. -youd have to administer nicotine in a higher concentration than cigarettes/nicotine patches/gum right? And it would have to be absorbed slower than any of the above methods..increasing risks?
 
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kaossalami said:
There are some quantenary nitrogen compounds that act similar to nicotine-stimulation

And this is what I mentt about neurotoxicity. -youd have to administer nicotine in a higher concentration than cigarettes/nicotine patches/gum right? And it would have to be absorbed slower than any of the above methods..increasing risks?
Click to expand...

neurotoxicity tends to refer to long term alterations of neuronal structure or function that usually persist in the absence of the causative agent, as distinct from acute toxicity or the acute toxic effects of an agent. For example parachloroamphetamine is neurotoxic but has low acute toxicity.
which is why I would be interested in seeing any evidence that nicotine is associated with neurotoxicity as opposed to acute toxicity, which is well known
http://en.wikipedia.org/wiki/Neurotoxicity
 
kaossalami said:
There are some quantenary nitrogen compounds that act similar to nicotine-stimulation

And this is what I mentt about neurotoxicity. -youd have to administer nicotine in a higher concentration than cigarettes/nicotine patches/gum right? And it would have to be absorbed slower than any of the above methods..increasing risks?
Click to expand...

neurotoxicity tends to refer to long term alterations of neuronal structure or function that usually persist in the absence of the causative agent, as distinct from acute toxicity or the acute toxic effects of an agent. For example parachloroamphetamine is neurotoxic but has low acute toxicity.
which is why I would be interested in seeing any evidence that nicotine is associated with neurotoxicity as opposed to acute toxicity, which is well known
http://en.wikipedia.org/wiki/Neurotoxicity

the quats you refer to don't usually cross the BBB very well as they are permanently charged so they are usually peripheral agonists only
 
I'd like to see some examples for such compounds...

Quaternary amines won't enter the brain, hence, not causing any kind of stimulation but just preripheral effects.

- Murphy

Edit: Vecktor just beat me to it.
 
I was doing some more research, and I have found that nicotine analouges are in fact used for a variety of things. SIB-1508Y is a nicotine based anti parkinson drug, and there has also been considerable research into conformationally constrained nicotine analouges. The toxicity of a parent compound is not going to be the same as its derivates, i.e. amphetamine MDMA and Methamphetamine all having varying levels of toxicity but the same base. Finally Increasing hydrophobicity would be a way to allow it to pass more easily through the BBB causing a more centrally acting effect, i.e. methylnicotinate, a drug currently under investigation.
 
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