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pti609 A non-addictive opioid

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Neuroprotection

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Apr 18, 2015
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I was browsing the web and came across the substance pti609. According to the small amounts of information I found, this compound is a potent agonist at the mu opioid receptor. However unlike most other agonists it is said not to produce tolerance or dependence even after long term use.
As I have only found very little out about this compound, it would be good if any of you could try to get more information and post it here particularly on its chemical formula make up or structure.
What do you think about this substance. Does it sound too good to be true?
The compound is also said notes to induce euphoria or reinforcement at therapeutic doses required for analgesic action. This should ameliorate the risk of psychological dependence, although I do really wish we could keep the euphoria with it, but without the tolerance.
 
It has never been tested in humans and there has only been limited testing in rodents. So no one really knows exactly what it will do in humans.
 
Seems to me like it might possibly still have affinity for TLR4 and there could be some health issues with that long term. Unless the reason for it's possible slow tolerance building is due to it's lack of affinity for TLR4 (See studies regarding potentiation of morphine analgesia with low dose naltrexone if you haven't before, it's interesting stuff).

I wonder if this substance would still cause the MOR to couple to Gs with chronic administration - not that low dose naltrexone couldn't have a chance at preventing that I think..
 
Cotcha Yankinov said:
Seems to me like it might possibly still have affinity for TLR4 and there could be some health issues with that long term. Unless the reason for it's possible slow tolerance building is due to it's lack of affinity for TLR4 (See studies regarding potentiation of morphine analgesia with low dose naltrexone if you haven't before, it's interesting stuff).

I wonder if this substance would still cause the MOR to couple to Gs with chronic administration - not that low dose naltrexone couldn't have a chance at preventing that I think..
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I think this substance has a novel way of avoiding tolerance build up, this is activation of the mu opioid receptor by interaction with a protein called fillimin A.
It would be disappointing however if this substance still has agonist affinity at the tlr4 receptor, although that problem may be easily solved by altering the molecular structure are rather cool administering a tlr4 antagonist such as the dextral isomers of Naloxone and naltrexone.
On the other hand what is your opinion on the developments of opioids with out the euphoric component. Do you think it would be possible one day to make a euphoric yet non-addictive opioid?
I remember creating a thread on this matter but I cannot locate it so I just want to know what you personally think.
 
MOR is first mostly coupled to inhibitory Gi/o, but with chronic mu agonism they switch to excitatory Gs (and thus a lot of the issues with tolerance - because the MORs coupled to Gs have higher affinity, low dose naltrexone can preferentially block these and reverse the coupling) but anyways the reason why MOR couple to Gs is due to an interaction with filamin-a.... So this drug might be quite interesting.. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628740/
(Sorry if you already know this)

I would kill for some dextro-naltrexone...

I'm not sure if there is any way to make opiates that have efficacy for pain without the euphoria, maybe MOR subtypes? I'm actually deficient in knowledge regarding opiate receptors :(

I think between NMDA antagonists, CCK antagonists, blocking the inflammatory receptors like TLR4 (I think there is more than just toll like receptors implicated in the inflammation that mediates tolerance, although I'm not sure if we should think that inflammation is mediating tolerance too much anymore now that we know naltrexone is really interfering with filamin a??) I mean I know inflammation is mediating tolerance to its efficacy for pain. But idk about euphoria...

One issue that could limit euphoria from opoids is compensation by the GABA neurons that the opoid receptors inhibit, and I suppose what's beyond that, and beyond that and so on, until you finally get to the point where biological activity is actually creating a feeling and altering conscious experience, which I would love to know about but I don't think we have the first clue about how chemical reactions and such lead to euphoria...

Sorry for rambling lol I haven't slept, hope this was helpful :)
 
I see now when you said non addictive you might not have meant a drug that doesn't have tolerance, but I don't know about a drug that doesn't have withdrawals if you're used to all that euphoria you think there would be some degree of compensation of cells downstream of the opiate receptors and those cells would kick your ass when you're sober methinks
 
Cotcha Yankinov said:
MOR is first mostly coupled to inhibitory Gi/o, but with chronic mu agonism they switch to excitatory Gs (and thus a lot of the issues with tolerance - because the MORs coupled to Gs have higher affinity, low dose naltrexone can preferentially block these and reverse the coupling) but anyways the reason why MOR couple to Gs is due to an interaction with filamin-a.... So this drug might be quite interesting.. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628740/
(Sorry if you already know this)

I would kill for some dextro-naltrexone...

I'm not sure if there is any way to make opiates that have efficacy for pain without the euphoria, maybe MOR subtypes? I'm actually deficient in knowledge regarding opiate receptors :(

I think between NMDA antagonists, CCK antagonists, blocking the inflammatory receptors like TLR4 (I think there is more than just toll like receptors implicated in the inflammation that mediates tolerance, although I'm not sure if we should think that inflammation is mediating tolerance too much anymore now that we know naltrexone is really interfering with filamin a??) I mean I know inflammation is mediating tolerance to its efficacy for pain. But idk about euphoria...

One issue that could limit euphoria from opoids is compensation by the GABA neurons that the opoid receptors inhibit, and I suppose what's beyond that, and beyond that and so on, until you finally get to the point where biological activity is actually creating a feeling and altering conscious experience, which I would love to know about but I don't think we have the first clue about how chemical reactions and such lead to euphoria...

Sorry for rambling lol I haven't slept, hope this was helpful :)
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Thanks the info you provided was helpful As always
It's good you're getting some sleep, sleep has been shown to enhance the function of the opioid system.
 
I think what people here are seeking is an opioid that is reinforcing but that does not promote compulsive use. Such a thing is probably not possible. People can get addicted to natural rewards like gambling and sex, which produce reinforcement that is much weaker than is found with opioids.

If a novel opioid is activating the mesolimbic dopamine system then it is probably going to produce sensitization and craving. It may not produce a discontinuation syndrome, which would certainly be a plus, but I don't see why it couldn't engender compulsive use.
 
The issue of craving and developing cues could indeed become pathological - I guess co administration with a a3b4 nicotinic antagonist might help...
 
There is a compound with similar properties, look up IBNtxA and this article.

roi said:
No update for 6 years? There must be a reason.
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Having analgesics as potent as or more potent than morphine enter the mainstream market is not in the interest of big pharmaceutical companies, that's for sure. As devastating as opioid dependence is, I'm sure the addictive effect is not something they mind as it adds in great benefits.

It's interesting though, could it be the non-addictive opioid scientists have been looking for since the great disappointment in heroin and then all those kappa agonists/partial mu agonists/antagonist like nalorphine, pentazocine etc.?
 
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adder said:
Having analgesics as potent as or more potent than morphine enter the mainstream market is not in the interest of big pharmaceutical companies, that's for sure. As devastating as opioid dependence is, I'm sure the addictive effect is not something they mind as it adds in great benefits.
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I know that this is a pretty common view, and it may be true for some drug companies like Purdue Pharma who markets oxycotin. But there are many pharmaceutical companies that don't make any money off opioids and have no financial incentive to hold back products that could potentially make a lot of money and deprive their competitors of market share. Investors love to throw money at small biotech firms that own the IP to new drug entities.

There could be a multitude of reasons why PTI-609 stalled. I would guess that it was just a screening hit, meaning that it is not necessarily a good lead compound. Pharmaceutical companies would want to play around with the SAR to optimize ADME and the synthesis procedures.
 
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just started a WP page on it. Reminds me of DAMGO. Thanks.
 
serotonin2A said:
PTI-609 doesn't produce conditioned place preference.
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Does it produce conditioned place aversion?

I'm curious how withdrawal effects preference of location. When in withdrawal will an animal tend to stay towards the area where the drug is administered and withdrawal is relieved - and if so might they display conditioned place aversion for areas of the cage where withdrawals were not relieved?

In other words, in some cases where an animal has repeated withdrawals, will they be motivated to be towards the area where the drug is administered because of negative consequences and not just positive reward? Sorry I'm wording this horribly.
 
Cotcha Yankinov said:
Does it produce conditioned place aversion?
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They didn't test it after chronic treatment, so CPA couldn't be used as a measure of withdrawal.

Cotcha Yankinov said:
I'm curious how withdrawal effects preference of location. When in withdrawal will an animal tend to stay towards the area where the drug is administered and withdrawal is relieved - and if so might they display conditioned place aversion for areas of the cage where withdrawals were not relieved?

In other words, in some cases where an animal has repeated withdrawals, will they be motivated to be towards the area where the drug is administered because of negative consequences and not just positive reward? Sorry I'm wording this horribly.
Click to expand...

In CPA studies the opioid is given before putting the animals in the test environment. So there isn't an area of the test environment where the opioid drug is administered.
 
Does anyone have any knowledge of the chemistry of this compound for example what elements it is made up of And what is its chemical formula is
 
Neuroprotection said:
Does anyone have any knowledge of the chemistry of this compound for example what elements it is made up of And what is its chemical formula is
Click to expand...

I had a short back & forth with a member of Wikimedia Commons who draws molecular 2D skeletal SVG images for Wikipedia and we, perhaps dismissively and ahead of ourselves, came to the conclusion that the chemical structure has not been made public as of yet.
 
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