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Selective Antagonists at Adeonsine A2A Receptor

Captain.Heroin

Captain.Heroin

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Why aren't we using them yet? I understand some are still in development, but shouldn't this be a thing? adenosine A2A antagonism is primarily implicated in the stimulant effects of caffeine with antidepressant effects, "but A1 and A2A are both required to replicate caffeine's effects in animals" (source). Why not skip A1 activation all together? Are stimulants less euphoric when the heart isn't surging?

Thoughts?
 
I guess the most important question to ask is what new adenosine antagonists would be used for? A drug has to be approved for a specific indication and has to offer some benefit over existing drugs. Making a new drug that can compete with caffeine in terms of efficacy, safety, price, etc would be challenging.
 
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A2A antagonists could have some drawbacks, for example A2A antagonists block the effects of BDNF on attenuating nicotinic a7 mediated responses in the hippocampus

https://www.ncbi.nlm.nih.gov/m/pubmed/18495895/

I assume A2A blockade could have deleterious effects for some mental health conditions, triggering hypomania/mania in bipolar patients for example.

Insomnia could also be an issue (although it's complicated what adenosine receptor mediates what effect, I can't remember), but on the other hand with narcolepsy, if caffeine helps those people then maybe A2A antagonists could help them a bit.
 
Cotcha Yankinov said:
A2A antagonists could have some drawbacks, for example A2A antagonists block the effects of BDNF on attenuating nicotinic a7 mediated responses in the hippocampus

https://www.ncbi.nlm.nih.gov/m/pubmed/18495895/

I assume A2A blockade could have deleterious effects for some mental health conditions, triggering hypomania/mania in bipolar patients for example.

Insomnia could also be an issue (although it's complicated what adenosine receptor mediates what effect, I can't remember), but on the other hand with narcolepsy, if caffeine helps those people then maybe A2A antagonists could help them a bit.
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How is this (1st paragraph) an issue?
 
Enhancement of a7 in the hippocampus could be good for Alzheimer's (https://www.ncbi.nlm.nih.gov/m/pubmed/22200627/) where there is atrophy of the hippocampus. There is also atrophy of the hippocampus in depression, but who knows just how signicant a role A2A antagonism could actually play therapeutically in increasing hippocampal long term potentiation (essentially growth of connections). In addition, enhancement of a7 could be good for schizophrenia https://www.ncbi.nlm.nih.gov/m/pubmed/17349863/ and schizophrenics are frequently heavy smokers because it helps alleviate some symptoms.

As far as the negative effects, I'm a bit torn now. I suppose it's possible that excessive LTP in the hippocampus could contribute to developing a trauma/aversive memory related disorder like PTSD (due to enhanced recall of the aversive memory or reduced extinction of averse memories, although that may not be the case for a7 specifically https://www.ncbi.nlm.nih.gov/m/pubmed/26688111/), or contribute to developing substance use disorders (due to enhanced association of context cues with the reinforcing effects). Hard to say though. Maybe the effect of A2A antagonism on nicotinic receptors/BDNF is not actually that strong.

At any rate, I highly doubt people could get much sleep with an A2A antagonist in their system at night. A2A antagonism also has other effects on the release of neurotransmitters, who knows what this could mean as far as risk for developing anxiety disorders and such.
 
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Heh, I'm completely on the other end of that spectrum. Just a bit of coffee and I start shaking and my extremities get so cold, won't sleep at all if I have coffee even in the morning.

For what it's worth, A1 adenosine receptor activation in the lateral preoptic area can mediate wakefulness. I can't recall what the active constituent of coffee has for affinity for the different adenosine receptors, but in general A2A is moreso for sleep if I recall correctly.
 
Cotcha Yankinov said:
Heh, I'm completely on the other end of that spectrum. Just a bit of coffee and I start shaking and my extremities get so cold, won't sleep at all if I have coffee even in the morning.

For what it's worth, A1 adenosine receptor activation in the lateral preoptic area can mediate wakefulness. I can't recall what the active constituent of coffee has for affinity for the different adenosine receptors, but in general A2A is moreso for sleep if I recall correctly.
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Adenosine A2A receptor has been shown to interact with Dopamine receptor D2.[64] As a result, Adenosine receptor A2A decreases activity in the Dopamine D2 receptors.
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https://en.wikipedia.org/wiki/Adenosine_A2A_receptor

also please refer to...

https://en.wikipedia.org/wiki/Adenosine_receptor#Comparison_of_subtypes
 
serotonin2A said:
I guess the most important question to ask is what new adenosine antagonists would be used for?
Click to expand...

I'm not sure how that's the "most important question", but I am thinking that caffeine is great but targeting the A2A receptor specifically would help create a better stimulant. I like caffeine and would like something without the other various effects at the other receptors.

Does literally no one feel what I'm going for here?
 
Putting aside my personal reservations about caffeine, I think some people could benefit from an A2A antagonist for various reasons, but if it's going to cost many millions (if not billions) to bring the drug to market, then it may have to get approved for Parkinson's movement issues or something rather than approved as a stimulant for some sort of fatigue syndrome like CFS or narcolepsy, because the latter groups of people could just use coffee while Parkinson's patients might need something more specialized, or with a shorter half life so you can be functional during the day and then attempt to sleep at night.
 
Captain.Heroin said:
I'm not sure how that's the "most important question", but I am thinking that caffeine is great but targeting the A2A receptor specifically would help create a better stimulant. I like caffeine and would like something without the other various effects at the other receptors.

Does literally no one feel what I'm going for here?
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I understand that it would be helpful to have a caffeine replacement. But would you pay 10-20x the current price of caffeine to buy a new drug that produces basically the same effect, but with unknown long-term safety? I don't think any company is going to spend hundreds of millions of dollars to develop a drug to compete on the OTC caffeine market.

The only reason why a drug company would develop a caffeine replacement is to pursue a therapeutic indication, because then it would be Rx-only, allowing them to make enough profit to recoup the development costs. Hence why I raised the question of which indication to pursue.
 
The pharma industry seems to be self regulating in the sense that drugs that are worth pursuing for profit are pursued. So I would guess either A2A antagonists will indeed be pursued or they are unprofitable (compared to pursuing other drugs) to bring to market.

I really only see Parkinson's as a probable indication. It would be hard to recoup costs unless you could charge a lot for a medication, and you're going to be able to charge a lot more for an A2A antagonists as a Parkinson's med instead of an ADHD med.
 
Cotcha Yankinov said:
The pharma industry seems to be self regulating in the sense that drugs that are worth pursuing for profit are pursued. So I would guess either A2A antagonists will indeed be pursued or they are unprofitable (compared to pursuing other drugs) to bring to market.

I really only see Parkinson's as a probable indication. It would be hard to recoup costs unless you could charge a lot for a medication, and you're going to be able to charge a lot more for an A2A antagonists as a Parkinson's med instead of an ADHD med.
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Narcolepsy? Any additional thoughts?

I can't imagine the pharmaceutical industry not pursuing this.
 
I think narcolepsy is believed to be due to (autoimmune) degeneration of wakeful orexin cells, these cells form a wakefulness projection that results in release of various neurotransmitters across the brain - I don't know if you'd be able to compensate for the loss of those wakefulness cells with blocking adenosine receptors. But if adenosine antagonism was helpful for narcolepsy, I imagine it would be noted that caffeine helps.

I think the issue is the sheer amount of money required to bring a drug to market. It might change a bit with the whole trump's FDA appointee thinking that we should let drugs come to market as long as they've proven safe thing. Which is ridiculous because no drug is safe, its just all about risk vs. benefit ratio, and with no known benefit ratio its just bleh, potato.
 
Captain.Heroin said:
Narcolepsy? Any additional thoughts?

I can't imagine the pharmaceutical industry not pursuing this.
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They are but it takes time to develop new drugs. Even after a good candidate is identified and found to be therapeutically useful, development can be derailed in phase II or III by a variety of factors. Furthermore, it isn't enough to be efficacious, new drugs usually have to offer some benefit over existing therapeutics. So unless there is nothing else available, as years pass it gets harder and harder to move new drugs through the pipeline.
 
serotonin2A said:
Furthermore, it isn't enough to be efficacious, new drugs usually have to offer some benefit over existing therapeutics. So unless there is nothing else available, as years pass it gets harder and harder to move new drugs through the pipeline.
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Care to share any thoughts on the Trump FDA appointee wanting to fast track drugs by not needing proof of efficacy before they hit the market? http://www.forbes.com/sites/patrick...-progressive-approval-for-drugs/#14aa519a1c34

"The first potential FDA chief appointee leaked by the Trump transition team is Jim O’Neill. Managing director of Peter Thiel’s Mithril Capital, O’Neill has publicly supported proposals to do away with the FDA’s requirement for phase 2 and 3 trials. Instead, he favors “progressive approval” of drugs and other medical technologies.

O’Neill would not be the first FDA head to favor progressive drug approval. Andrew von Eschenbach developed this system when he served as FDA chief. But during his tenure, Eschenbach was not able to put such a far-reaching reform into practice in the US. The Japanese, though, saw the value of Eschenbach’s plan. They now use it for regenerative medicine. Japan legalizes therapies following proof of safety. Once a drug is in use, companies can move to phase 4. This means they monitor their patients and disclose efficacy data regularly."

So does this mean zero placebo controlled/double blind efficacy data?

At least it increase the ability of smaller companies to bring drugs to market as well as increases the ability of drugs for small populations to be brought to market, but do you have faith that the general efficacy of drugs won't take a huge fall?
 
Cotcha Yankinov said:
Care to share any thoughts on the Trump FDA appointee wanting to fast track drugs by not needing proof of efficacy before they hit the market? http://www.forbes.com/sites/patrick...-progressive-approval-for-drugs/#14aa519a1c34

"The first potential FDA chief appointee leaked by the Trump transition team is Jim O’Neill. Managing director of Peter Thiel’s Mithril Capital, O’Neill has publicly supported proposals to do away with the FDA’s requirement for phase 2 and 3 trials. Instead, he favors “progressive approval” of drugs and other medical technologies.

O’Neill would not be the first FDA head to favor progressive drug approval. Andrew von Eschenbach developed this system when he served as FDA chief. But during his tenure, Eschenbach was not able to put such a far-reaching reform into practice in the US. The Japanese, though, saw the value of Eschenbach’s plan. They now use it for regenerative medicine. Japan legalizes therapies following proof of safety. Once a drug is in use, companies can move to phase 4. This means they monitor their patients and disclose efficacy data regularly."

So does this mean zero placebo controlled/double blind efficacy data?

At least it increase the ability of smaller companies to bring drugs to market as well as increases the ability of drugs for small populations to be brought to market, but do you have faith that the general efficacy of drugs won't take a huge fall?
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It is not possible to seperate issues of safety and efficacy -- safety is a relative measure that is evaluated based on the indication. There is always a trade-off between safety and efficacy. Additionally, safety is really not fully evaluated until phase IV. Earlier studies should pick up effects that are very common and widespread, but rare side-effects are often missed.

What are considered disqualifying side-effects is very different for drugs used to treat cancer vs. itching.
 
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serotonin2A said:
It is not possible to seperate issues of safety and efficacy
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Do you believe the loss of phase III trials will be significant? It seems like if the pure safety data is incomplete and you don't have placebo controlled trials to prove pure efficacy, we're bringing drugs to market in which the risk-benefit ratio is really unknown. That being said, I, probably more than most, am willing to roll the dice and apply in vitro knowledge to in vivo. I just hope that pharmaceutical companies don't see this as a major cash cow. I'm certain that there are numerous caring and thoughtful scientists within the pharmaceutical industry, but I do worry that the higher-ups are more concerned with profits than putting out efficacious drugs.

If we skip phase III and go straight to phase IV, will there be double blind/placebo controlled studies shortly thereafter, and it will only be the people taking the particular drug at the beginning of phase IV that will be venturing into the unknown?

I understand that the issue of placebo control is only of real concern when it comes to mental health (I'm assuming placebo doesn't affect cancer or HIV patients etc.) so could you see a separation of procedure when it comes to getting a mental health drug approved vs. a more somatic drug?

Thanks for any thoughts.
 
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