ABT 594 and similar

vecktor

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Does anyone have hard information as to why Abbot dropped the nicotinic agonist ABT 594 in phase 2 trials?
it is an interesting molecule based on the extremely dangerous poison and potent non opioid analgesic Epibatidine, the toxin originally from an Ecuadorian poison frog (200x as strong as morphine hype). Epibatidine has a minimal theraputic index effecting the heart and causing convulsions followed by death at doses only slightly higher than the analgesic doses.

ABT 594 was Abbots modification of the epibatidine lead compound



They have a newer nicotinic agonist ABT 894 in human trials, perhaps that was why the earlier ABT 594 was dropped. but I don't think they have released the structure, has anyone any guesses as to the structure of ABT 894??

Next question, which subtypes of the nACh receptor are interesting in terms of releasing DA from where it is co-located with dopaminergic neurons?
I know that ibogaine is relatively selective on one subtype in contrast to the rest of its diverse and messy pharmacology.
 

vecktor

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nuke said:
What was the indication for the drug? Analgesic?

edit: Not only that, but also ADHD...huh?
http://clinicaltrials.gov/ct/show/NCT00429091?order=1
there are European human trials going on with ABT 894, for neuropathic pain and ADHD. seems like an odd combination.

in fact there seem to be a lot of nicotinic beasties from Abbot in phase 1 safety trials, ABT-107, ABT-560 all in partnership with Neurosearch who incidentally are also trialling their own phenyltropane (WIN type compound) tesofensine.

I think that some of these selective nicotinic agonists, probably the ones that didn't make it to trials have fun potential..
 

Ham-milton

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I dunno- some of these nicotinic drugs probably have abuse potential. That clinical trial has "history of substance abuse" and "nicotine replacement therapy" as exclusion criteria.

I can't imagine a recreational nicotinic drug, though. They always say that nicotine is as addictive as heroin. I don't think the people who're saying that have tried heroin, though.
 

mad_scientist

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Hmm i remember seeing the original report when they pulled ABT-594 from the trials, they cited an unacceptable incidence of side effects, not abuse potential or anything. Can't remember what side effects they were but didn't sound like serious life threatening stuff to me, was like headaches and nausea or something. I'll see if i can track down the document, it was online somewhere....
 

Riemann Zeta

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I wonder if nicotinic agonists, without the peripheral effects of nicotine itself, would be decent stimulant compounds? Nicotine itself is a stimulant, but it is very hard to hit just the right dose for central stimulant effect without other effects.
 

5-HT2

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vecktor said:
Next question, which subtypes of the nACh receptor are interesting in terms of releasing DA from where it is co-located with dopaminergic neurons?
Both alpha4/beta2- and alpha7- containing nAchRs play a significant role in modulating dopamine release from dopamine neurons (DANs). a4b2-containing receptors on the axon terminals of DANs act as a high-pass filter that enhances phasic dopamine signals. They are also located on the axon terminals of ventral midbrain GABAergic interneurons that inhibit DANs. Because a4/b2-containing nAchRs desensitize so quickly, after an initial short activation, nicotine produces a longer-lasting depression of GABA release onto DANs. In addition, nicotine acts on alpha7-containing receptors located somatodendritically on DANs to excite them.
 

kidamnesiac

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stupid question, what defines a nicotinic drug? the ortho(?), meta(?) (going by the location of the nitrogen, not sure of the nomenclature) group on the pyridine ring?
or is it strictly based upon interaction with said receptors?
 

Jamshyd

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Riemann Zeta said:
I wonder if nicotinic agonists, without the peripheral effects of nicotine itself, would be decent stimulant compounds? Nicotine itself is a stimulant, but it is very hard to hit just the right dose for central stimulant effect without other effects.
Another problem with Nicotine is the whole "rapid desensitization" thing, although admittedly I am not very well-versed in what this does.

I have used Nicotine purely as a stimulant before in the form of patches (that solves your dosing problem :)) and it works VERY well. So good, in fact, that it perfectly substituted for amphetamine for me and helped me with my withdrawal.
 

Riemann Zeta

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I have also used pure nicotine in the form of patches (and gum) as a stimulant. It was many years ago (my patch experience)--I remember it did kick me in the ass, but it wasn't calming or focusing like speed and it produced all sorts of unpleasant PNS effects. Then, when I took the patch off, around 28 hrs later, I got really sick and wanted to puke. This surprised me, as I did smoke cigarettes at the time, so it was not just intolerance to nicotine.
 

5-HT2

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kidamnesiac said:
stupid question, what defines a nicotinic drug? the ortho(?), meta(?) (going by the location of the nitrogen, not sure of the nomenclature) group on the pyridine ring?
or is it strictly based upon interaction with said receptors?
Yeah, it's strictly based on the interaction with nicotinic (ionotropic) acetylcholine receptors.

Jamshyd said:
Another problem with Nicotine is the whole "rapid desensitization" thing, although admittedly I am not very well-versed in what this does.
In pharmacology, desensitization is the loss of responsiveness to the continuing or repeated dose of a drug.

As I described in my previous post, the rapid desensitization of a4/b2-containing receptors may actually play a key role in the psychoactive effects of nicotine.
 

JacksinPA

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ABT-894 (Abbott Labs): an alpha-4-beta-2 neuronal acetylcholine receptor agonist. It must have taken quite a bit of molecule fiddling to get from epibatidine to ABT-894.

Anyone familiar with any work done on the effects of nicotine analogs? Such as (R)-nicotine as opposed to the naturally occurring (S)-enantiomer? Or things like pyridine ring chlorinated derivatives? I'd be concerned about smoking halogenated derivatives as the halogens would have a tendency to pyrolyze off as HX, which would give you a real smoker's cough.
 

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