Arylcyclohexylamines as androgens/estrogens/STEROID MIMICS?

[sekio]

So like most good chemists I'm always thinking about similarities. I remembered the old legend of, people on PCP are superhuman and able to lift cars, they get crazy aggressive, etc, and the like. I thought about its weird possible neuroregenerative processes. I also noted the fact that both arylcyclohexylamines and steroids are bulky, multicyclic compounds with at least one aromatic center and some little polar bits as decorations.

The first spot I go is to Chemspider, cause it has this LASSO thing, which predicts protein affinities. Here's what comes up.
Phencyclidine

NSFW:

PCE

NSFW:

3-HO-PCP

NSFW:

3-MeO-PCP

NSFW:

4-MeO-PCP

NSFW:

4'-OH-PCP

NSFW:

Diphenidine

NSFW:

(s)-Ketamine

NSFW:

So... this is interesting. I know that stuff like tamoxifen and diethylstilbestrol kind of remind me of diphenidine.

Could this explain some of the ... strange effects of PCP and its analogs? Is this a red herring? Does Ashy Larry have bitch tits from smoking sherm? Does getting whacked on methoxy-diphenidine cure breast cancer?

 

[endotropic]

Really not a lot out there on these sorts of interactions. PCP has the most:

Estradiol counteracts the effects of PCP on memory:
http://www.ncbi.nlm.nih.gov/pubmed/22561127
http://www.ncbi.nlm.nih.gov/pubmed/18208936

Rates of PCP self administration is determined by menstrual phase (primates):
http://www.ncbi.nlm.nih.gov/pubmed/17156834

There's a whole bunch more showing that PCP changes the levels of one sex hormone or another, but none of these studies address direct vs. indirect effects. So with all that searching I can say you could be on to something, maybe.

Do you have any info on what that LASSO search does exactly?

 

[blueberries]

I'm still not sure what this LASSO score means, as I've not encountered it in pharmacology before. From Wikipedia: "LASSO - A similarity based virtual screening tool that uses elements of eHiTS scoring function to identify bioactive molecules in large libraries of compounds."

'eHiTS' seems to be an "algorithm that is designed to find the global minimum energy pose of ligands in proteins' binding pockets". So what does this mean for the hormones they're binding to and enhancing? Does a higher score indicate more enhancement of such hormones or less (as with receptor (Ki) binding affinities, which is what I'm used to)?

Sorry I'm not up to date on this terminology but I'm no scientician (in the regular sense, anyway!) and as a regular dissociative user this is fairly high on my interest level.

However as far as I've noticed, over the last four years of my on and off dissociate use, I've noticed no increase or decrease in hormone levels but I reckon it would be hard to tell if it were in such slight amounts. In fact when on PCP, I was carrying home a few bags of shopping from Sainsbury's and was incredibly dissatisfied at the amount of 'superhuman strength' given as implied by various media sources. Actually I had to stop several times as it was so heavy!

 

[SONN]

You're such a genius. It almost hurts

Your brain is boldly going where no brain has gone before %)

This is beyond flabbergasting

 

[Solipsis]

Seems like there is a big difference between momentary performance (like super strength) and muscle generation or even degeneration.

I think that the high 'strength' performance while under the influence of compounds like PCP or (the ones I am actually experienced with) 3-MeO-PCP and 3-MeO-PCE is a matter of reduced inhibition and perhaps combined with dopaminergic action. I'd say the effects on inhibition are essential or key, and it is important that this effect is not thwarted by sedation or anaesthesia which is the case with a nice dose of ketamine (well S-ketamine actually), and say downers like alcohol or GHB. Those also act disinhibiting, but there are probably other effects countering that.
Isn't it also true that some if not most people with retardation or Down's syndrome can also show high strength performance because they may lack control which is strongly associated with inhibition. One might say 'they don't know their own strength' when they might lash out.

Other effects enhancing or augmenting the increased strength may be reduced proprioception or noniception, which may also allow performance requiring strength to go past safety limits that normally attenuate our movement and actions.

I'm not really sure what effects steroids / hormone-like compounds have on actuating performance (lol roid rage?), but is not a big part of their potential increased muscle generation which simply boosts muscle mass and power?
My point being that once a (manic) dissociative wears off, there is probably a lot of muscle damage from going past those limits. Someone said in PD that some rhabdo is normal with dissociatives, so that might explain it... if not some other metabolic effect.

Surely I am interested to hear more about other theories, but we would probably need decent evidence to go with theories that are more complicated than the relatively basic ideas I just mentioned.

 

[sekio]

LASSO is software that uses neural networks to predict the activity of various drugs. Scores closer to 1 mean the drug fits the profile better, scores closer to zero mean it's not a good fit. So this seems to suggest that for instance PCP and 3-HO-PCP would be a very good estrogen receptor agonist, ketamine is a glucocorticoid and retinoid X receptor agonist, PCE is a glucocorticoid, etc.

This says nothing about their actual affinities and dosages, it just means that the molecules fit a certain SAR.

 

[blueberries]

Ah, thanks for clearing that up. I was a bit worried about my recent 3-MeO-PCP usage for a minute there.

Now that it makes sense, I really want to know the binding affinities! Also I knew Diphenidine was a bit of a weird drug but damn not that weird! I would go into my ideas about it being an SDRA but it's not really the time or place. Perhaps though it was just my menstruation that made me feel like shit in the morning!

Another thing; that HIV protease activity...could it be a treatment for HIV, or on the other hand an HIV enhancer :S

Also could S(+) Ketamine's Glucocorticoid activity attest to it's great anti-depressive properties? I mean if it binds very tightly it would increase gene transcription (and altering genes if I'm getting what it does correctly) therefore creating highly agonised D2 receptors, and in turn causing lasting anti-depression. I would say the same for PCE too but for the moment we cannot tell whether it would bind tightly or not and barely any human testing has been done with it, so it could also be a very effective anti-depression agent.

 

[MeDieViL]

Ah, thanks for clearing that up. I was a bit worried about my recent 3-MeO-PCP usage for a minute there.

Now that it makes sense, I really want to know the binding affinities! Also I knew Diphenidine was a bit of a weird drug but damn not that weird! I would go into my ideas about it being an SDRA but it's not really the time or place. Perhaps though it was just my menstruation that made me feel like shit in the morning!

Another thing; that HIV protease activity...could it be a treatment for HIV, or on the other hand an HIV enhancer :S

Also could S(+) Ketamine's Glucocorticoid activity attest to it's great anti-depressive properties? I mean if it binds very tightly it would increase gene transcription (and altering genes if I'm getting what it does correctly) therefore creating highly agonised D2 receptors, and in turn causing lasting anti-depression. I would say the same for PCE too but for the moment we cannot tell whether it would bind tightly or not and barely any human testing has been done with it, so it could also be a very effective anti-depression agent.

Its antidepressant effects are mediated by a nmda subunit, selective agonists currently being developed have a similar effect.

 

[sekio]

Another thing; that HIV protease activity...could it be a treatment for HIV, or on the other hand an HIV enhancer :S

I think HIV protease means it blocks HIV's ability to break down or create proteins. It's a good thing.

Ketamine and efavirenz as HAART?

 

[MyExcuse]

For the record, for what it is worth, I have been able to do incredible things on methoxetamine and phenibut that would not have been possible with sober control over my body.

I've always thought it was just a reduction in some limiting part of my brain combined with the "paradoxical" stimulation of the drug. Would be interesting to know if there is anything deeper to it all.

 

[MeDieViL]

For the record, for what it is worth, I have been able to do incredible things on methoxetamine and phenibut that would not have been possible with sober control over my body.

I've always thought it was just a reduction in some limiting part of my brain combined with the "paradoxical" stimulation of the drug. Would be interesting to know if there is anything deeper to it all.

Incredible things?

 

[Abject]

I'd just like to bring up that strength is our muscles ability to contract/tense. An average build has the potential to lift extremely heavy things but we don't know how.
Strength and sarcoplasmic hypertrophy are two very different things.

I do remember reading that dissociatives (or DXM in particular?) actually accelerates/promotes muscular atrophy, though I could be way off on this thought.

 

[Zeds(NCO2CH2CH3)2]

Excellent post sekio

http://www.ncbi.nlm.nih.gov/pubmed/14530949

Ketamine obviously interacts with mu receptors ala a modified HPA(hypothalamic-pituitary-adrenal axis) negative feedback loop stimulated by change in nmda receptor function. Sounds weird? Look at this from the opposite end.

http://forum.opiophile.org/showthread.php?17864-A-Collection-of-Novel-Unscheduled-Opioids

http://i263.photobucket.com/albums/ii129/haribo1_photos/Bromidol.png

Notably sc17599 the compound is an opioid drug derived from a steroid derivative ironically enough IT LOOKS JUST LIKE pcp and the above mentioned examples.

By connecting these two ends we see that there is a connection between opiate and steroid function and HPA as well as nmda and HPA and the binding site it VERY nonpolar and apt to accept cyclohexane rings.... see the basic steroid structure and deduce Molecular surface area as well as the length.

There is research on nmda and the hpa but I never realized the total connection.. Honestly the steroid and pcp and somewhat opioid pharmacophore maybe more similar than we realize

Zeds dead

 

[SONN]

http://www.ncbi.nlm.nih.gov/pubmed/15573019

"Glutamate-hypothalamic-pituitary-adrenal axis interactions: implications for mood and anxiety disorders."

that study suggests Zeds dead is right about the HPA thing. Fascinating stuff, I hope more research is done on different drugs and their effects on the HPA in the near future. I wish figuring out how to optimize the various systems within our brain was a more popular topic in science.

 

[clubcard]

Affinity ≠ agonist although the body does have a habit of reusing signalling chemicals; inside & outside BBB.

If you want to take a pop at Big Pharma - just remember that intelligent design is out and these probability calculations means that an average drug will first be 1 of 10000, then 1 of 100 then 1 out of 2-3.... then it MIGHT get used.

MASSIVE screening for 1 effect - nobody has even thought of screening for multiple actions.

ALL the 'blockbuster' meds arrived via intelligent design. Looking at modern medication, it's a mess. HUGE costs to cover the screening.

The greatest output, from the greatest pharmaceutical chemist was Paul Janssen (Greatest Belgian ever?) and I advise people to look through his methodology. From 1 scaffold he got haloperidol, fentanyl (and a host of other opiates). He just took a scaffold and worked on it.

 

[dopamimetic]

This makes me wanna try real PCP I don't know how much about these horror stories is true, but with reasonable dosing all the arylcyclohexylamines I know of were manageable (and each fascinating in its own way), including 3-MeO-PCP. The diphenylethylamines might be another thing though.

 

[Epsilon Alpha]

Damn never noticed this thread before, my understanding was that PCP strength was due to gamma motor neuron inhibiton. Block those and your body doesn't know how contracted your muscles are.

I can't find the source but one of my pharmacology profs mentioned that it has something to do with NAChR inhibiton

 

[clubcard]

Of course, swapping the cyclohexane ring for a morpholine or thiomorpholine ring works. See Eur. J. Med. Chem 34 (1999) 125-135

The thiophene has a better LogP. Another find that's apparently to much like hard work!

 

[SONN]

okay I'm just gonna give this anecdotal report.

earlier today I combined 3meopcp with icariin and magnolol and honokiol, alll of which have supposed effects on your hormones.

(magnolol and honokiol stimulate steroidogenesis-- specifically glucocorticoids IIRC)

according to your lasso thing 3meopcp interacts with the same exact receptor!

maybe other people will attribute it to the effects of 3meopcp but I swear there was some kind of interesting synergy going on and I currently feel like my hormones just went through some type of transformation here.

edit: so I just took a bunch more magnolol and honokiol, and I definitely feel more effects in general than I usually feel.

today I just drank a little coffee, took some magnolol and honokiol, did some 3meopcp and I'm gonna work out soon I will update after

edit2: that was an intense workout, I would recommend it to anyone else trying to become superhuman