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Thanked Posts by Gun Lover
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2018-02-14 at 6:19 PM UTC in Smoking ants in a bongAre you fucking retarded?
Everyone knows the best high comes from banging wasps.The following users say it would be alright if the author of this post didn't die in a fire! -
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.The following users say it would be alright if the author of this post didn't die in a fire! -
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.The following users say it would be alright if the author of this post didn't die in a fire! -
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.The following users say it would be alright if the author of this post didn't die in a fire! -
2018-02-16 at 1:17 AM UTC in Lol.I loathe seeing these fucking 90lbs-soaking-wet cunts being dragged along by their 150lb dog. They have no control over the animal.
It's always good to bring nig medicine when you take your dog to the park.
Also: lolThe following users say it would be alright if the author of this post didn't die in a fire! -
2018-02-15 at 1:05 PM UTC in Abandoned Neutrons ...In Space!As usual, a mastapieceThe following users say it would be alright if the author of this post didn't die in a fire!
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2018-02-15 at 4:34 AM UTC in Florida shooting: at least 17 killed in high school attackThe US is a crazy place. I still need to buy a couple of those bump stocks.The following users say it would be alright if the author of this post didn't die in a fire!
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2018-02-10 at 1:56 AM UTC in does everyone here use meth?
Originally posted by lightray how can you predict the effects of a compound?
In medicinal chemistry there exists the concept of bioisosteres. These are different "chemical substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to another chemical compound."
This basically means that the substituents on the backbone of many active drugs can be swapped with similar functional groups. In this case, I am suggesting the replacement of a methyl -CH3 group for a trifluoromethyl group -CF3.
Fluorine is one of the smallest elements; it is similar in size to hydrogen while being very polar and electron withdrawing. These 3 fluorines all one one carbon actually cause the -CF3 group to behave somewhat like a halogen (Cl, Br, I) substituent. Since we know that the chloro-substituted analogue is active and decent, I believe the -CF3 substitution will lead to a new active drug.
https://en.wikipedia.org/wiki/Mecloqualone
Basically:
You can replace the methyl with a halogen and get a novel active drug, why not replace the methyl with its closest size bioisostere? The main difference between the classic drug and what I propose is a bit of halogen character, which is not a problem for activityThe following users say it would be alright if the author of this post didn't die in a fire! -
2018-02-09 at 5:26 PM UTC in The Retardest Thread: Fashionably Late Edition.
Originally posted by RestStop I think diseases/disorders tend to consume all aspects of the sufferer's life if they let it. Not that it should be common but it definitely is. It's also a huge crutch to keep from doing things or a poor excuse as to why one hasn't done certain things. "Oh I have slight headaches sometimes..that's why I'm 30 and a virgin". LOL niqqaz!
Wish I had the thanks buttonThe following users say it would be alright if the author of this post didn't die in a fire! -
2018-02-09 at 2:35 AM UTC in The Retardest Thread: Fashionably Late Edition.
Originally posted by SpatianHaigency How have you been
Hey dude
I've been better mentally, but overall things are looking up. I met my current girlfriend right before zoklet went under. We got our chemistry degrees and went off to grad school together. The semester before grad school I got really disillusioned with pharmacological research and abandoned my dreams of becoming a psychopharmacologist or medicinal chemist. I am studying polymer chemistry, instead. It's useful and there's jobs. That same semester I also met up with Bunghole at a science conference in Denver and got him super high. That guy is a fucking brilliant chemist.
I got my first non-minimum wage job as part of the degree program. The school and/or your major professor pay you for 5 years to get a phd. My girlfriend gets paid 30k to get her degree, and I get bit less. It's not an uncomfortable wage when this state is so cheap.
I built a couple of high end gaming computers for my girlfriend and I with my surplus money about a year before altcoin mining exploded. Last May I decided to begin mining with 3 GPUs and I gambled all of the profits on a coin called Antshares at the price of around $6. Antshares was rebranded as NEO, and became a top 10 cryptocurrency in less than a year. I won't sell for the foreseeable future, but I'd be sad to cash out with less than six figures. Staggering return for running a program in the background 24/7 and paying twice the power bill. I think for a few years into the future GPUs will continue to print money. After stumbling into this dumb luck, I've become keen on searching for other good investments as a hobby. Fuck getting a real job if I never have to.
I also spend a lot of my time trying to figure out where to move to. I'm thinking about leaving the US after the phd. I could move just about anywhere I wanted with my girlfriend. Any country will take phds in their 20s. We are planning a lot of traveling to Europe & Canada for next year to see how we like it.
HSA, I hope you're doing better man, last I saw you were deep in the benzos.
Originally posted by Malice Were you molested as a child or something? How does it affect you?
I wasn't. People who I care about were. Is that an acceptable answer?
By the way, I'm proud of you for going outside more than once a month. It's been surreal to come back to this community of degenerates and see just how much has changed.The following users say it would be alright if the author of this post didn't die in a fire! -
2018-02-08 at 6:35 PM UTC in The Retardest Thread: Fashionably Late Edition.I've been lurking this shithole because reddit gives me cancer. It's good to see some of you around here.The following users say it would be alright if the author of this post didn't die in a fire!