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Posts by Gun Lover
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2018-02-23 at 4:36 PM UTC in C O L O R A D O B O Y SBuy most of your weed off craigslist. The stores are cool to visit, but it's way cheaper to get a guy from craigslist to deliver.
You can totally eat wax, just make sure it's been decarbed. -
2018-02-23 at 3:58 PM UTC in lol this nigga is a drug addict
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2018-02-22 at 7:25 PM UTC in lol this nigga is a drug addictI can't click that video after seeing the thumbnail
Originally posted by 哈哈你看不懂中文 It's so absolutely fucking ridiculous that we prescribe amphetamines to people. I will never understand why it isn't more common to use nootropics for people who have ADHD.
Protip: amphetamine is a highly effective nootropic
I never actually had ADHD, but I like to take my amphetamine script when the right occasion arises. Nothing unhealthy about occasional, low-dose usage. -
2018-02-21 at 7:22 PM UTC in weed addiction at critical levelsThat happens to my girlfriend, especially when we are doing dabs 24/7
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2018-02-20 at 2:21 AM UTC in structure-activity relationships
Originally posted by lightray but wouldn't the 5ht2a unit in a homodimer and heterodimer be the same? the only difference is that the heterodimer also has a glutamate receptor
Absolutely not. You've gotta realize that these dimers have an inherent allosteric effect upon one another. They are essentially locked together at a junction at the intracellular space. It is not at all accurate to say that receptor = homodimer = heterodimer. When one part changes shape, the other changes too.An allosteric receptor–receptor interaction exists in this complex since mGlu2 receptor activation produces an increase in the affinity of hallucinogenic 5-HT2A agonists for the 5-HT2A protomer binding site (Gonzalez-Maeso et al., 2008). A bidirectional receptor–receptor interaction is present since 5-HT2A agonists reduce the affinity of mGlu2 agonists for the mGlu2 protomer binding site. It is of substantial interest that the allosteric receptor–receptor interactions in these heteroreceptor complexes are dysregulated in postmortem brains from schizophrenia subjects
It seems to me that endogenous glutamate binds to the dimer, which increases the binding affinity of some, but not all 5-HT2A agonists. A ligand like serotonin binds more poorly after glutamate activation while drugs like LSD bind with great efficacy. But just because a drug has high affinity does not mean it gives efficacy. Lisuride is an example that binds strongly to the dimer without activating the second messenger pathway that makes you trip. -
2018-02-20 at 1:10 AM UTC in structure-activity relationships
Originally posted by Zanick I don't have a sophisticated understanding of pharmacokinetics, so this may be a silly question, but I'm curious: is there a way to block the nonpsychoactive serotonin pathway, allowing it to bind to the other?
You could block the nonpsychoactive serotonin pathway, but then you'd probably die. It won't just go to the other path. -
2018-02-20 at 1:04 AM UTC in structure-activity relationships
Originally posted by lightray https://en.wikipedia.org/wiki/5-HT2A_receptor#Agonists
"Newer findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT2A–mGlu2 and not by monomeric 5-HT2A receptors"
https://en.wikipedia.org/wiki/Metabotropic_glutamate_receptor_2#Role_in_hallucinogenesis
"Many psychedelic drugs (e.g. LSD-25) produce their effects by binding to the oligomerized complexes of the 5HT2A and mGlu2 receptors"
I would assume not. If a chemical can bind to to 5-ht2a-mglu2, it will do so. Blocking the regular serotonin pathway won't make it hop over to the heterodimers, and blocking the regular serotonin pathway will make it impossible for psychedelia to even occur, since for psychedelia all receptors in the heterodimer need to be activated
Looks like the science has progressed a little bit since I last looked. This helps explain functional selectivity, but I don't think it does anything for SAR predictions.
Be careful with trying to quantify how many sites must be occupied before the receptor is activated. It is not always necessary for every site to be occupied, and largely depends on the stage of the receptor's life (extent of phosphorylation at that receptor at that time).
Originally posted by lightray in simpler terms: for a drug to be a psychedelic, it has to bind to both a certain serotonin subunit and a certain glutamate unit. Which I think would imply that the mechanism of action of psychedelics overlaps with dissociatives? I dunno
It only has to bind to the serotonin unit. The glutamate receptor is activated by glutamate naturally present throughout your body.
I wouldn't be surprised at all if this receptor dimer thing is tied to the psychedelic effects of ketamine and other NMDA antagonists. I'd go so far as to bet that it does. -
2018-02-20 at 12:04 AM UTC in MelatoninI owe you a thanks, §m£ÂgØL.
Melatonin is fucking weird. Not too surprised I was wrong. -
2018-02-20 at 12:02 AM UTC in structure-activity relationshipsThe thing about serotonin 2A is that even if you know the drug is safe & shows high receptor affinity, you still have to deal with the enigma of functional selectivity.
You can have a drug that displays affinity & efficacy at 5-HT2A but does not induce psychedelia. This has to do with the receptor inducing two different signaling pathways -- one makes you trip but the other doesn't. I have never heard of a way to predict the drug's preference for one pathway or another. There isn't a way to know without measuring it, and there is no obvious trend to me. Even then that answers only one question -- it says nothing of the pharmacokinetics.
Serotonergic psychedelics really are a crapshoot. You can have fun thinking up stuff, but there's no good way to know its merits as a drug without tasting it. -
2018-02-19 at 11:46 PM UTC in structure-activity relationshipsBeing able to predict such things isn't really a matter of "will the chemical modification retain activity" and more of "is the chemical modification a bad idea?" Knowing the basics of organic chemistry and molecular biology is essential so that you can ask yourself questions like:
Will the substitution be too polar or too fatty?
How will that effect absorption, distribution, metabolism & excretion?
Will it play nice with your metabolic enzymes?
Will it remain a similar steric size?
Do similar substitutions within the same drug scaffold lead to desirable drug?
You can have the best, most accurate answer to all of these and still wind up with a dud. It happens all the time in pharma research where there is basically unlimited manpower and resources.
In the case of serotonin 2A, you should peruse pihkal & tihkal. You can infer what positions can be substituted at all, what substitutions seem most safe and effective, then play around from there.
What you won't be able to ascertain without synthetic organic chemistry knowledge is how difficult your proposed drug will be to make. It's easy to draw exotic things that look good on paper. It's an entirely different ordeal to actually obtain the stuff.
Originally posted by Lanny Yeah, I'm not sure, I see people talking about anticipated effects from 2D primary structure diagrams on drug forums pretty often too. I'm pretty skeptical of it but they're much simpler molecules than I ever see from the computational perspective so it could be the 3D structure isn't as important there. Either from fear of chemistry or natural complexity of the domain I don't know but CS people tend to be of the opinion that pharmacology is totally unknowable from primary structure. There's plenty of examples of where it clearly is, but again, not sure if that's globally true or just for a certain class of molecules. I think gun lover mentioned starting a PhD in something pharma related so I'd be interested to hear from someone who presumably knows more about the subject.
The reason chemists use 2D skeleton drawings is because they are simple & convenient. They are idealized structures existing in total isolation; they are succinct and easy to compare. But chemists understand that molecules are 3-D and that the preferred orientation of the molecule is always going to depend on its chemical environment. So when we're talking about all of these structures it is understood that their preferred conformation dynamic and varied upon things like temperature, pH, buffer effects, solvent effects, etc. You will pay tens of thousands of dollars in supercomputer costs in order to get a 10 nanosecond window into "realistic" drug-receptor docking. But then your initial parameters have to be impeccable, or else any result one way or the other is effectively null.
I actually quit pursuing this research, because, aside from a few scaffolds to play with, no one really knows what is a viable psychoactive or not. The best minds and supercomputers struggle to pump out safe and effective drugs. The experiments suck to actually run. -
2018-02-19 at 12:39 AM UTC in What's your IQ?Sploo, I'm not going to waste my time with your test this time. You know I'm smarter than you.
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2018-02-18 at 8:09 PM UTC in The Retardest Thread: Fashionably Late Edition.
Originally posted by Malice Are you in the US? Where can I buy this? It sounds like it could be good for school (only 4 days a week), paired with a benzo, until I can meet with a psychiatrist.
There are weight loss clinics in the US that still prescribe it; that's where the ones I got originated.
I'd look for the sketchiest one you can find that doesn't accept insurance. Also, it's heavenly with etizolam. -
2018-02-18 at 7:21 PM UTC in The Retardest Thread: Fashionably Late Edition.
Originally posted by Malice I want to tone down the trolling, as I don’t want people to have that perception that I’m overly aggressive and insane.
Good plan. You've gone off the deep end lately.
Originally posted by RestStop I haven't. Haven't even heard of it. For reference I love Modafinil and pretty dislike Addie's if that's any insight. If I haven't mentioned I LOVE METH.
It's been illegal everywhere for a good while, but I'm pretty sure you'd really like it. I got ahold of some phendimetrazine which is a prodrug of phenmet. It was everything I could want in a stimulant: increased focus, pronounced euphoria, greatly reduced fatigue, and no comedown to speak of.
It managed all that while having a twinge of that MDMA glow that just makes you happy to be alive. I can't imagine the pure stuff.
Wikipedia says the Swedish users of phenmet preferred it to both amph and meth. The Beatles are probably the most famous users of it. -
2018-02-18 at 7:08 PM UTC in The Retardest Thread: Fashionably Late Edition.
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2018-02-18 at 6:42 PM UTC in when's this wall of trump's being made?
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2018-02-18 at 6:26 PM UTC in Melatonin
Originally posted by 哈哈你看不懂中文 Look into efficacy studies. Low dose is the way to go. I personally didn't feel shit from melatonin till i got 500ug pills. It helps me sleep. Also intensifies my dreams
No shit? I always got a good effect from 3mg and up, but the increased dose wasn't more effective. I always thought the 300-500mcg tabs were bordering on homeopathy. -
2018-02-18 at 6:23 PM UTC in The Retardest Thread: Fashionably Late Edition.Got the doctor to prescribe me Dexedrine. It sure beats that gross overstimulation with both enantiomers. Pure d-amp is pretty damn relaxing.
Next year I'm gonna push for desoxyn -
2018-02-16 at 8:35 PM UTC in meth smell/tasteFreebase amphetamine fucking reeks
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2018-02-16 at 7:53 PM UTC in i'm an alcoholic. :(Gross.
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2018-02-16 at 3:54 AM UTC in Natural spring water
Originally posted by BRiCK THe most fucked up thing about fluoride, in my opinion, is that they add it to almost everything these days. Even baby formula.
But BRiCK, they say that fluoride is good for your teeth!
Although fluoride is one of minerals used to construct the tooth enamel crystals, there is a lot more to it. The proteins that facilitate tooth growth basically let crystals form, and them bring them to the correct place on the tooth. Once in place, the proteins are removed by enzymes. Where does fluoride come into play? It bonds with calcium. And calcium is what activates these tooth building proteins/enzymes.
Due to their inhibition, the tooth building proteins are no longer broken down like theyre supposed to. This covers some of the tooth surface, not allowing other tooth building proteins to lay down crystals
You're fooling yourself if you really believe this