opioid receptors mediate the antidepressant-like activity of hesperidin

[allone]

Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test - PubMed

The opioid system has been implicated as a contributing factor for major depression and is thought to play a role in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of hesperidin in the mouse forced...

pubmed.ncbi.nlm.nih.gov

how reliable can hesperidin really be considering it comes from, oranges & lemons. it seems the peel playing the role which basically means, humans do not get much at all. the vital point of this though is, its in vivo study regardless of being on rats, it does bring more attention to it as bioavailable compound.

 

[Skorpio]

Ip administration, while it does usually go through first pass metabolism by being taken up into the portal vein, can bypass early metabolic reactions that occur in the stomach yielding results in animals that don't translate to humans.

Furthermore these compounds are found at very low levels in plants compared to the doses used in rodents (even scaling for rodent metabolism).

I think the value in this study is suggesting a scaffold that can be used to create kappa antagonists (I assume) that are more druglike than plant flavanoids.

 

[allone]

yeah you can do some adjustments to the chemical, cook up something new that can work. if someone has the knowledge time and care enough that is.

 

[G_Chem]

What would be some potential “adjustments” one can see with this molecule?

-GC

 

[Skorpio]

What would be some potential “adjustments” one can see with this molecule?

-GC

I've got no idea really, the main things I would try doing are improving stability and pharmacokinetics. I would look into what parts of it are involved in binding the kappa receptor, and try to work around that primarily.

I'd get rid of the flavanoid ring system for something less metabolically labile, and also see if the aglycone is the active agent (then you wouldn't have to deal with glycoside metabolism).

I'm not really a medicinal chemist, so probably lacking some nuances but those are the things that jump out at me.

 

[Rectify]

SKORPIO
7-(1-methyl-piperidin-4-yl)-oxy-(2S)-5-methoxy-(3',4'-methylenedioxy)-flavan-4-one

Like Sands Through The Hour Glass, So Are The Days Of Our Lives.

 

[Skorpio]

SKORPIO
7-(1-methyl-piperidin-4-yl)-oxy-(2S)-5-methoxy-(3',4'-methylenedioxy)-flavan-4-one

Like Sands Through The Hour Glass, So Are The Days Of Our Lives.

Shit, I'm flattered. Also forgot the key med-chem principle of "throw a methelenedioxy" on that bitch.

 

[plumbus-nine]

After tianeptine it wouldn't surprise me when a very slight activation of opioid (delta?) receptors would be antidepressant. Or are there other targets known for tianeptine?

 

[Skorpio]

After tianeptine it wouldn't surprise me when a very slight activation of opioid (delta?) receptors would be antidepressant. Or are there other targets known for tianeptine?

Tianeptine is pretty selective for the mu opioid receptors (as tested by binding assay). Furthermore, the mu opioid receptor is necessary for the antidepressant effects of tianeptine, but not the delta opioid receptors. This leads me to believe that any other effects mentioned are not really germane to its effects.

I have read things about tianeptine being a biased agonist (activating the g-protein pathway without as much engagement of beta arrestins). The basis for this hypothesis is that tianeptine reverses morphine respiratory depression (which is classically via the beta arrestin cascade), and antidepressant effects occur still in beta arrestin knockout mice. An alternative hypothesis could be that tianeptine is a partial agonist (which would explain the reversing morphine respiratory depression), and that beta arrestin signaling isn't involved in antidepressant effects, so knocking out that protein wouldn't impair them.

I don't think you will see too many drugs that are plain delta agonists (in the same way you don't see any ghb site agonists, they all have affinities at inhibitory receptors as well). This is due to the fact that these receptors are fairly good at inducing seizures when unopposed, so while a touch of delta affinity may add a special flavor to a mu agonist, delta agonism on its own is likely anxiogenic and convulsant (same situation with ghb receptor and gaba b receptors).

 

[allone]

thats interesting you brought up tianeptine. its still to be completely figured out and might be banned eventually. some states have done that already. it might not leave much room for research as this chemical has been used since the 60s and people still cannot figure out all it does. im interested in this as i have been using it for 15 years on and off. i started it like i started kratom for getting off opiates. both, kratom and tianeptine were virtually unknown in the US back in the day. now both of them are abused!

 

[plumbus-nine]

i started it like i started kratom for getting off opiates. both, kratom and tianeptine were virtually unknown in the US back in the day. now both of them are abused!

You might want to look into dissociatives if you haven't yet done so. High doses of memantine and some of the RCs (2F- and DCK, anyone will do but you want the longer acting ones, K lasts too short) repeatedly allowed me to make a complete pain- and symptomless jump from opioids, and I was at 600mg morphine a day. No diarrhea, no lethargy, no nothing. Makes the whole dependence stuff look strange, when SSRIs are wayy worse than morphine for me, as long as I have access to dissociatives. I have some kratom here but no need for it!

 

[Skorpio]

this chemical has been used since the 60s and people still cannot figure out all it does

In 2017 this paper blew the lid off for the tianeptine mechanism of action. They did a really elegant job showing that it is the mu opioid effects that are needed for antidepressant effects of tianeptine.

Later papers have supported these findings (always a good sign), and demonstrated subtleties with the various opioid circuits activated by tianeptine, but it's broad mechanism of action is pretty well supported (I tend to believe gene knockout studies, as when they knock out relevant genes the drug effect is totally abolished; conversely knocking out other genes willl have little effect).

The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor - PubMed

Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors, are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously...

pubmed.ncbi.nlm.nih.gov

 

[Jabberwocky]

You might want to look into dissociatives if you haven't yet done so. High doses of memantine and some of the RCs (2F- and DCK, anyone will do but you want the longer acting ones, K lasts too short) repeatedly allowed me to make a complete pain- and symptomless jump from opioids, and I was at 600mg morphine a day. No diarrhea, no lethargy, no nothing. Makes the whole dependence stuff look strange, when SSRIs are wayy worse than morphine for me, as long as I have access to dissociatives. I have some kratom here but no need for it!

Sorry to jump in like this but... @plumbus-nine can you walk me through a reasonable dosing regiment or some "memantine protocol" for reducing withdrawal? To not put this one off topic would you be so kind and post in this thread? Thanks.

 

[allone]

In 2017 this paper blew the lid off for the tianeptine mechanism of action. They did a really elegant job showing that it is the mu opioid effects that are needed for antidepressant effects of tianeptine.

Later papers have supported these findings (always a good sign), and demonstrated subtleties with the various opioid circuits activated by tianeptine, but it's broad mechanism of action is pretty well supported (I tend to believe gene knockout studies, as when they knock out relevant genes the drug effect is totally abolished; conversely knocking out other genes willl have little effect).

The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor - PubMed

Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors, are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously...

pubmed.ncbi.nlm.nih.gov

this is what i find very interesting and you can google as there are several papers regarding tianeptine being beneficial in opiate respiratory depression; https://pubmed.ncbi.nlm.nih.gov/26068549/

which is so unique considering tianeptine itself in high doses IS an opiate. how does it not cause respiratory depression like all other opiates? contradictory so, it reverses it. should one consider using low to moderate dose tianeptine for opiate overdose? that is a very interesting mechanism tianeptine has

since its rat studies, ill vouch personally for this as i was in the hospital being drugged up on morphine and i still used tianeptine which actually made it more comfortable meaning, i wasnt nodding off. in fact, i didnt sleep well at all which was unusual on an opiate.

 

[Skorpio]

Tianeptine in all doses is an opiate, just high doses get you high.

There could be two possible explanations for this (which I havent seen a lot of evidence pointing one way or another).

First, tianeptine could be a partial agonist with a higher affinity than morphine (like buprenorphine). In this case tianeptine would kick morphine off the receptors but produce less activation than morphine.

Second, (this is what a lot of papers hypothesize but it is also a trendy topic so im still wary) tianeptine could be a biased agonist. There is a paradigm (which I currently believe) that opioids engage multiple downstream signal Cascades from the mu opioid receptor (gi protein based and beta arrestin based). The beta arrestin pathway is thought to contribute to respiratory depression, so a biased agonist that only activates the gi pathway would reduce respiratory depression when given concurrently with morphine due to competing for receptor binding with morphine but not causing the degree of respiratory depression of morphine.

I currently haven't seen any killer experiments giving weight to either pathway (but I haven't exhaustively scoured the literature).

 

[allone]

thanks, thats interesting. it also sobers me up from ethanol intoxication which is something else altogether i suppose. it could be related to its glutamatergic modulation; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902200/ and https://www.nature.com/articles/tp201430

this compound deserves a lot more studying and its extremely underrated. perhaps it might affect the liver a bit too much to be very reliable long term? but i havent really seen concrete evidence of this yet. just speculations.

 

[plumbus-nine]

Sorry to jump in like this but... @plumbus-nine can you walk me through a reasonable dosing regiment or some "memantine protocol" for reducing withdrawal? To not put this one off topic would you be so kind and post in this thread? Thanks.

The more the better. I can't give you real dosage advice because my tolerance is naturally weird and due to prolonged use I tolerate absurd dosages (like 120+mg and I read of others taking even more) but the effect is still pronounced in lower doses. Brain fog tends to be a problem for part of the people and maybe related to nACHr antagonism. It can be a chance to stop other addictions at the same time, like nicotine, pregabalin.
What opioid and for how long? An option can be to use memantine besides the opioid to keep tolerance at bay. The RCs like deschloroketamine work too but they of course are more recreational. I would avoid K, it's too short acting and puts a strain otno your bladder.

 

[Skorpio]

glutamatergic modulation; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902200/

This paper is from the dark days before the mu opioid mechanism was tested. There aren't any convincing experiments supporting the glutamate hypothesis, and there haven't been followup studies in the past 12 years.

I wouldn't put too much weight on their claims.

 

[allone]

This paper is from the dark days before the mu opioid mechanism was tested. There aren't any convincing experiments supporting the glutamate hypothesis, and there haven't been followup studies in the past 12 years.

I wouldn't put too much weight on their claims.

ok thanks for this input. but im pretty certain this compound has some glutamatergic action based on my own experiences and observations. i assume there havent been repeated studies on this subject because its worthless, meaning no investment, profit from such niche studies.
but i really appreciate your input ALOT on this. most people do not even bother researching it much at all each time i bring it to the topic. thanks for this man! but there is a long way to go when it comes to this, ill tell you that much!

 

[Neithman]

Tianeptine is pretty selective for the mu opioid receptors (as tested by binding assay). Furthermore, the mu opioid receptor is necessary for the antidepressant effects of tianeptine, but not the delta opioid receptors. This leads me to believe that any other effects mentioned are not really germane to its effects.

I have read things about tianeptine being a biased agonist (activating the g-protein pathway without as much engagement of beta arrestins). The basis for this hypothesis is that tianeptine reverses morphine respiratory depression (which is classically via the beta arrestin cascade), and antidepressant effects occur still in beta arrestin knockout mice. An alternative hypothesis could be that tianeptine is a partial agonist (which would explain the reversing morphine respiratory depression), and that beta arrestin signaling isn't involved in antidepressant effects, so knocking out that protein wouldn't impair them.

I don't think you will see too many drugs that are plain delta agonists (in the same way you don't see any ghb site agonists, they all have affinities at inhibitory receptors as well). This is due to the fact that these receptors are fairly good at inducing seizures when unopposed, so while a touch of delta affinity may add a special flavor to a mu agonist, delta agonism on its own is likely anxiogenic and convulsant (same situation with ghb receptor and gaba b receptors).

There are studies showing that the G-protein pathway also contributes to the respiratory depressant effects of opiids. Beta Arrestin Knockout Mice still display respiratory depression after morphine administration