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    pti609 A non-addictive opioid 
    #1
    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.
     

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    #2
    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.
     

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    #3
    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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    #4
    Quote Originally Posted by Cotcha Yankinov View Post
    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..
    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.
     

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    #5
    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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    #6
    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
     

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    #7
    Quote Originally Posted by Cotcha Yankinov View Post
    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
    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.
     

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    #8
    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.
     

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    #9
    The issue of craving and developing cues could indeed become pathological - I guess co administration with a a3b4 nicotinic antagonist might help...
     

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    #10
    http://adisinsight.springer.com/drugs/800033607

    No update for 6 years? There must be a reason.
     

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    #11
    There is a compound with similar properties, look up IBNtxA and this article.

    Quote Originally Posted by roi
    No update for 6 years? There must be a reason.
    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.?
    Last edited by adder; 29-05-2016 at 23:26.
     

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    #12
    Quote Originally Posted by adder View Post
    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.
    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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    #13
    Bluelighter Nagelfar's Avatar
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    just started a WP page on it. Reminds me of DAMGO. Thanks.
     

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    #14
    For pretty WP references, go to https://en.wikipedia.org/wiki/Specia...ection-gadgets and enable "ProveIt". Or use http://reftag.appspot.com/doiweb.py.
     

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    #15
    Bluelighter Nagelfar's Avatar
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    Quote Originally Posted by roi View Post
    For pretty WP references, go to https://en.wikipedia.org/wiki/Specia...ection-gadgets and enable "ProveIt". Or use http://reftag.appspot.com/doiweb.py.
    Thanks roi
     

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    #16
    PTI-609 doesn't produce conditioned place preference.
     

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    #17
    Quote Originally Posted by serotonin2A View Post
    PTI-609 doesn't produce conditioned place preference.
    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.
     

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    #18
    Quote Originally Posted by Cotcha Yankinov View Post
    Does it produce conditioned place aversion?
    They didn't test it after chronic treatment, so CPA couldn't be used as a measure of withdrawal.

    Quote Originally Posted by Cotcha Yankinov View Post
    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.
    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.
     

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    #19
    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
     

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    #20
    Bluelighter Nagelfar's Avatar
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    Quote Originally Posted by Neuroprotection View Post
    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
    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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    #21
    It is undoubtedly in one of the patents. The problem is figuring out which compound it is. You might be able to figure it out by the process of elimination.
     

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    #22
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    Nagelfar, also had to think about DAMGO when reading the title wonder why this isn't researched further, or derivates of it.

    Well, it's highly interesting that (if I understand it correctly) the most relevant binding site of naloxone/naltrexone is different from mu/delta/kappa and this (pentapeptide region on FLNA) is combined here with mu agonist activity.

    Would administering pti-609 to opioid dependent people/animals cause a precipitated withdrawal, and what if one waits long enough before, like when switching to buprenorphine? If not, this could prove ideal to taper off opioids ...

    But of course the possible place aversion is relevant. For me the graph already looks like place aversion, both tested dosages went below vehicle, it's just one test though.

    I got accidentally exposed to a tiny dosage of naloxone nasally (1.5mg maybe), when I wasn't opioid dependent but took a high dose of 40mg/d of memantine. This was an hour of pure, distilled anxiety, depression and sad/hopelessness. Never ever felt so lonely and cold in my life. No physical symptoms because I wasn't dependent, no physical pain either, so I wonder very much about what it actually did. The inverse agonism of mu might be dysphoric by itself, also the displace of endorphins, but the alcoholics seem not to feel much from taking a huge 50mg naltrexone ... so it must have to do with the memantine, probably with instantly shutting the D2 agonism off (I had withdrawal from memantine later too, which surprised me and it wasn't easy, not comparable to naloxone by any means though.)

    If pti-609 is devoid of reward or even downright dysphoric as naloxone, then I'd imagine it might be the neuroleptic of opioids- something nobody would take unless he's in strong pain (and in such a condition there are probably already a lot of endorphins at work, and it could be strongly dysphoric too)?

    Maybe we'll find out sooner or later by RC people doing the human testing for them

    On the other side, by doing the inverse of the non-mu side of naloxone, maybe one could create a non-opioid euphorisant lacking the physical side of opioids, or?

    (Just my thinking - it is possible to take the withdrawal and even tolerance development off opioids to some extent [show memantine or dextromethorphan studies for combined pain treatment etc] but relief of pain always raises the level of confidence because everyone of us has some minor or major worries, pains etc. at any point of our life. Only strictly pheriperally acting things like topical local anesthetics lack physical effects. Even paracetamol gets abused..)
     

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    #23
    Bluelight Crew polymath's Avatar
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    Combined mu agonist/delta antagonists are another class of compounds that are thought to produce analgesia without development of tolerance and dependence. Delta receptor blockage also seems to reduce cocaine self-administration. There seem to be many ways to slow down opioid tolerance development but none of them have been approved for real medical use, for whatever reason..
     

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    #24
    Quote Originally Posted by palmanita View Post
    But of course the possible place aversion is relevant. For me the graph already looks like place aversion, both tested dosages went below vehicle
    The error bars are very wide. The graphs are a bit misleading because the y-axis is truncated (it doesn't start at 0), which tends to make marginal effects appear larger.
     

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