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Pharmaceutical Chemistry: There's More in That Pill Than Drug and Ground Up Rock

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Letonna:
I have 9 ideas for a new lecture series. I'll list them below. I'll gauge interest in the irc channel if people want more. With all the talk of inactivity, I thought I might try to breath some life into the university.

Lecture Topics:
-Beta-Lactam Inhibitors
-Creams, Ointments, Lotions, Potions, Balms, and Powders
-Hormone and Steroid Therapy
-Phenethyamines: These ain't your grandpa's psychedelics.
-Therapeutic Sugar: Manitol, Glucose, Sucralose, Lactulose, and Sorbitol
-Non Enzymatic Drugs. The Red Headed Step Children of Pharmacology: PEG, Therapeutic Salts, simethicone, zinc oxide
-Herbal Medicine
-Aphrodisiacs
-Vaccines.






Beta-Lactamase Inhibitors, and Duct-Taping a Growing Problem




If you recall, in a previous, different lecture, I discussed antibiotics, and how they get their power chiefly as being critical enzymatic inhibitors. But, if you watch the news(or read), you likely have heard of antibiotic resistance. It is a problem that can’t really be comprehended with just half assd news reports and posters at your doctor's office.

The type of antibiotic resistance I’ll be talking about today is to a class of antibiotics called beta-lactams, specifically, penicillins and some others like:Penicillin(surprise), amoxicillin, ampicillin,piperacillin, ticarcillin.  These antibiotics interrupt cell division in cells with hard outer membranes, and essentially cause tears in their hard outer membranes until they explode under pressure.

What has been observed in the past half century is through artificial selection, cells who have a mechanism to break off the antibiotic from the enzyme survive the mass genocide of its peers. In the case of these antibiotics, it’s a new enzyme called Beta-lactamase. A enzyme whose sole job is to rip off antibiotic molecules from their target enzymes.

So, as is often the case in medicine, the most obvious solution is to reinhibit it. Beta-Lactamase inhibitors were introduced in the 70’s and 80, which inhibit the enzyme beta-lactamase.

So to recap, we have an enzyme, being inhibited by an inhibitor(antibiotic), but is susceptible to removal by a different enzyme, which we are inhibiting with a different enzyme inhibitor. Now, a curious mind might point out: “What if that new compound will itself become susceptible to removal by a new enzyme?” to which I say “God save us.”


Above Image: Tazobactam, the companion beta-lactamase inhibitor to piperacillin, seen below
Chemistry and pharmacology

Surprisingly, but perhaps not surprisingly, the chemical structure of beta-lactamase inhibitors is roughly the same as the antibiotics they protect. Notice from the image that the “lactam” rings are still intact, but instead, to the right of the penta ring we see some weird structures. These are meant to bind to key spots in the beta-lactamase enzyme, essentially paralyzing it.

In formulation, these drugs will usually come in formulation of 500mg, 1g, 2g, and really anything in between, with 100 mg ish of a beta-lactamase inhibitor. This is because there is less inhibition needed in the beta-lactamase inhibitors. The cell division process is much more laborious, so it hence has a higher dose of antibiotic than BLI.

It’s very likely you have taken a beta-lactam inhibitor and have not even known it. The widely popular prescription drug Augmentin is a combo pill consisting of(usually) 875mg of amoxicillin and a compound called clavulanic acid(or potassium salt) in 125 mg.

Clavulanic acid,seen above,  the companion Betalactamase inhibitor to Amoxicillin, seen belowAnother popular one, although only used in hospitals in the united states, is a drug called unasyn, or ampicillin and sulbactam. Ampicillin by itself hasn't been useful in a widespread clinical application in years, except in some pediatric cases. But combined with sulbactam, it's been given a second life. This combination drug is especially popular, because by the end of production, the cost is relatively low, and the patient may only pay upwards of 100 USD for a complete treatment.

Conclusion

Bacterial resistance will never go away, it will always be there as long as we are. Luckily we’re clever enough to think of quick fixes. I like to think of these drugs as the duct tape of medicine. Enough to stop the leak, but you’ll probably want to replace the pipe sometime before it breaks.

Red Mones:
Yay! I was hoping you would post more of these. They're very interesting.

bigbaldben:
I like these.  I'd be interested in learning more about SSRIs and Aminoketone if they are in your wheelhouse.  Or anti-depressants in general.

Letonna:
Phenethylamines: These Ain't Your Grandpa's Psychedelics



I this photo, you see my mostly empty book shelf. I’m still unpacking, but I got a lot of the important stuff on there. You’ll see some books I have for school, booze, and a book called PHIKAL. This book is very special to me. It’s one I’ve actually never read front to cover, and never will. It was a gift from a friend a few years ago.


Simply stating, it’s a book that is a step by step guide on how to make psychedelic drugs. The first third of the book is a semi fictional autobiography of the author's life, but the remainder is a step by step guide to making hundreds of psychotropic compounds. I’ve only read certain parts of it, and only refer to it once and awhile when I’m curious how the author describes a certain reaction. I really wish I had this book when I was taking organic chemistry because it’s all organic chemistry.[He wrote another book about another group of psychotropic substances he discovered but I don't have it.]

But how can such a thing be legal? Well, in many parts of the world it isn’t. Including some more developed nations like Australia. People have certainly tried to ban it for many years in the US, but they’ve also tried to ban the anarchist cookbook and that’s still around. Freedom of speech simply. The book doesn’t advocate for drug use or the distribution of drugs. It’s completely a chemical reference guide to a class of chemicals called phenethylamines. And even if you wanted to use it to make drugs to get you and your friends high, the language he uses is so dense, you need to have done extensive schooling to understand what the hell he is talking about.

I don’t own this book because I plan to make drugs, or teach people to make drugs, but because, pardon my language, it’s so fucking cool. It’s so rare to find a chemist, who not only made these drugs in his free time, but researched them extensively, cataloged them, tested them on him and his wife(she volunteered), but made a readily exercisable reference guide to them.

Anyway, to the science.


The above image is of phenethylamine. A very simple chemical consisting of 3 major parts. The aromatic benzene ring, a 2 carbon chain, and an amine group. This chemical alone is a little boring. It acts as a neurotransmitter in some parts of the brain, and is believed to play a role in dietary behavior and mental health. You can actually buy this drug as a herbal supplement. Between you and me it’s more or less ineffective in the concentrations sold, but we’ll save that for the herbal medicine lecture.

What happens when you start modifying this chemical (which is very easy and cheap to do) is it’s bioavailability and affinity for bonding to enzymes and receptors goes up drastically. Dr. Shulgin theorized he could make a drug so powerful, based off this design, you would only need a few molecules of it to get the high of a lifetime(he never succeeded before his death).


What’s so amazingly bizarre and truly amazing about these drugs is all of them do something slightly different. Through testing on himself he reported some of them helped him sleep, some made him hungry, some made him hallucinate, feel energized, taste amazing, feel happy, feel sad.

And he was only foreshadowing what recent medical discoveries have discovered. These drugs can be used for many things. In fact, one of them just got put on the market as an anti-obesity drug. And another as an ADHD medication. And another a treatment for asthma. And twice as many for depression.
Buproprion, or Wellbutrin, is a popularly prescribed phenethylamine used as a smoking cessation agent and antidepressant
I said earlier that additions and changes to the basic structure are pretty easy and cheap. And this is mostly true. Reagents used are simple things like dichloromethane, or phosphoric acid, or any number of small molecule reagents. Stuff you buy by the gallon. And they aren’t very hard reactions, simple pH shift, polymerizations, tautomerizations, and halogenating. I mention this because many pharmaceuticals are so expensive because the rare chemicals they use.

It’s some debate if these drugs will eventually become illegal. A lot of them are illegal, but many remain unclassified under the Scheduled Drug Act, mostly because so little outside of Dr. Shulgins work on them is known. Remember, that making them won’t get you in nearly as much trouble as distributing them. I’m sure someday they will be under more strict control, but for the meantime, they are the wild wild west of psyco-pharmaceuticals.

Dr. Alexander Shulgin

Lindisfarne:
Great lecture!  Great initiative!
 :clap:
More of this!

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