Kyotorphin

[Limpet_Chicken]

Cane across this rather intriguing compound on wikipedia whilst searching for other stuff pertaining to opioids, its a dipeptide, L-tyrosyl-L-arginine, and acts not via directly stimulating opioid receptors, but as an enkephalin (met-enkephalin specifically) secretagogue and by retarding degradation of same.

Presumably that means enkephalinase inhibitor in addition to its secretagogue properties.

How likely is this to be of some recreational use, being a releaser as well as enkephalinase inhibitor (which in the case of solely the latter mode of action I'd not expect to be recreational, making an analogy with the likes of FAAH inhibition and the endocannabinoid system, but being a releaeser also makes it a more complex picture.

And what I was really wondering, is seeing as met-enkephalin is produced via proteolytic cleavage of proopiomelanocortin, the same precursor that serves as a precursor for the melanocyte stimulating hormones, beta-endorphin and importantly, ACTH, whats the likelihood of a compensatory downregulation in POMC production and correspondingly, fucking over the HPA axis due to insufficient ACTH production and thus a pro-addisonian effect with continued use?

The unusual mode of action got me thinking, namely that it might make a useful detox type med for opioid users especially for things like PAWS. But then I thought of possible endocrine issues.

Whats the likeliehood of this kind of being being somewhat safer with regards to respiratory depression than classic opioids? seeing as how enkephalins are primarily delta opioid receptor agonists I'd hazard a guess that they wouldn't be particularly liable to that. And what do others think the chances are of it being likely with longer than intermittent or single dose use, doing nasty things to the HPA axis?

Chances are its not going to be orally active, being that its a peptide, but is it capable of penetrating the BBB in humans?

 

[Cotcha Yankinov]

When you say secretatogue, does that mean it causes leakage out of the vesicles?

But regarding POMC, I suppose if there is a mechanism by which met-enkephalin would cause inhibitory feedback control over POMC cleavage, it should be seen with other DOR agonists (assuming the control is mediated by DORs).

 

[serotonin2A]

Met-enkephalin is primarily synthesized from proenkephalin A. The Met-enk sequence is of course part of beta-endorphin, but the cells that synthesize POMC don't usually cleave it to Met-enk.

I recall that most opioid-R feedback regulation of POMC occurs via MOR.

 

[Limpet_Chicken]

by secretagogue, I meant inducer of release. Not sure how it does it on the molecular level yet.

Are neuropeptides like beta-endorphin and met-enkephalin even stored in vesicles? or is there another region of storage for the propeptide or prepropeptide and the needed fractions just cleaved off as and when required?

 

[serotonin2A]

by secretagogue, I meant inducer of release. Not sure how it does it on the molecular level yet.

Are neuropeptides like beta-endorphin and met-enkephalin even stored in vesicles? or is there another region of storage for the propeptide or prepropeptide and the needed fractions just cleaved off as and when required?

Neuropeptides are usually stored in large dense-core vesicles.

 

[Limpet_Chicken]

So whats the best guess as to whether its likely to induce downregulation of POMC? or are enkephalin levels independent of POMC, courtesy of its being important for other neurotransmitters of unrelated function, or at least, pretty distantly related, and an upregulation of enkephalinase more likely? as I've been getting very curious about kyotorphin, perhaps enough to give it a try in vivo, H aside I haven't experienced anything bar kratom with known and certain agonistic effects on DORs, unless you count H and the switch in affinities from MOR to DOR agonism exhibited by heroin in morphine-dependent or highly tolerant subjects. H USED to be your typical bog standard strong opioid for me, and since switching from oxy to morphine for my primary pain med, now its got a strange tweaky edge to it, akin to the oddball psychostimulant properties of alpha-chloromorphide.

Looking for things to compare alpha-chloromorphide to, since it was so completely....odd, and not in the least opioid-like as one usually thinks of (Mu) opioids. And some kratom does have hints, as does H,

 

[serotonin2A]

So whats the best guess as to whether its likely to induce downregulation of POMC? or are enkephalin levels independent of POMC, courtesy of its being important for other neurotransmitters of unrelated function, or at least, pretty distantly related, and an upregulation of enkephalinase more likely? as I've been getting very curious about kyotorphin, perhaps enough to give it a try in vivo, H aside I haven't experienced anything bar kratom with known and certain agonistic effects on DORs, unless you count H and the switch in affinities from MOR to DOR agonism exhibited by heroin in morphine-dependent or highly tolerant subjects. H USED to be your typical bog standard strong opioid for me, and since switching from oxy to morphine for my primary pain med, now its got a strange tweaky edge to it, akin to the oddball psychostimulant properties of alpha-chloromorphide.

Looking for things to compare alpha-chloromorphide to, since it was so completely....odd, and not in the least opioid-like as one usually thinks of (Mu) opioids. And some kratom does have hints, as does H,

They just published (early 2016) a trial with a selective DOR agonist and it didn't seem to produce any recreational effects. The study couldn't push the dose very high (to avoid seizures) but there weren't any hints of effects that you would find interesting.

Blocking enkephalinase produces analgesia but it is unlikely to be particularily fun. It is pretty well established that MOR activation is required for opioid-induced euphoria.

 

[Limpet_Chicken]

Do you have a link, or DOI number for that study?

And, from the seizure potential, that presumably means the ligand used was either a selective DOR1 or mixed DOR1/2 agonist?

I'm not necessarily looking for recreational effects, I am looking to find DOR agonist candidates specifically so I can make an in-vivo (cautious, of course, due to the potential for convulsant effects, obviously slowly ramping up doses from inactive levels) to alpha-chloromorphide. Because I really have gotten the curiosity bug about that stuff after my experiences with it. And again in the case of alpha-chloromorphide, I decided not to push the dose, due to beginnings of hinting that it may have turned out to be convulsant at higher doses. In fact I suspect it may well do so, although am most certainly not about to find out. I am insatiably curious, it is true, but I have my limits about what KINDS of things I wish to find out. And that I am having a seizure, is not, unsurprisingly, one of them (things I want to discover, that is, not limitations;P

There was quite obvious although mild and at the levels tested (will need to do further reruns, in order to remember what they were dose-wise, since I was expecting a MOR agonist at the time), harmless clonus of the distal extremities. And subjectively the only similarity with MOR agonists which were observable was it was capable of suppression of MOR agonist withdrawal owing to habituation to morphia and oxycodone.

Otherwise, it was at once both subtle but at the same time it was most certainly active, just not in any MOR-agonist opioid-like manner.

And the only subtype-selective DOR agonists I know o ff the top of my head that are very easily available are diamorphine (DOR1) and 6-MAM (DOR2) but only after an affinity switch in dependendcys fr

 

[serotonin2A]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5103283/

The classification of multiple DOR subtypes is being phased out because a single gene is responsible for all of the DOR binding sites (which is the current criteria for classifying receptor subtypes). DOR may be pharmacologically heterogeneous due to posttranslational modification, homodimers, heteromization, etc, but there probably aren't discrete DOR subtypes.

 

[Limpet_Chicken]

Well if not distinct DOR subtypes, then such as you mention, the likes of splice variants (look at MOR for instance, MOR1 specifically has quite a lot of alternately spliced isoforms. Morphine and heroin are differentially selective for different splice variant isoforms of MOR1 , which is believed to explain the incomplete cross-tolerance exhibited by heroin in a morphine user, or vice versa.)

Be it different subtypes, splice variant receptor isoforms, polymerized receptor complexes, the functional effect that some of the agonist ligands are pro-convulsant in excessive doses and some are not is significant enough in practise to mean at least some variety in DOR function/architecture/localization to be important and potentially worth exploring.

As I said, I am not as such, looking for new recreational substances, rather, searching to increase my knowledge, and if there be potentially useful DOR ligands, then so much the better. I'm just not expecting to find the next morphine or methamphetamine/cocaine. And through in-vivo trial, to make comparison to alpha-chloromorphide, seeing as how the latter is SO far outside the realms of what one would expect from a MOR agonist were I not physically dependent upon morphine/oxy/prope for long term pain relief and thus able to assess potential of opioidergic type agonists for suppression of withdrawal, I honestly wouldn't have been able to tell anyone that alpha-chloromorphide had anything to do with the opioidergic system in the slightest.