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The Big and Bangin' Pseudo-Advanced Drug Chemistry, Pharmacology and More Thread, V.2

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Pomzazed, could you expand in more detail on the SAR of CB1 ligands. More importantly, what is required for antagonist activity. Afaik CB1 spontaneously switches between active and inactive states; rimonabant stabilises the inactive state of CB1, and thus could be considered an inverse agonist.

https://en.m.wikipedia.org/wiki/Can...nist#/media/File:Rimonabant_Pharmacophore.png

Are the marked aa residues in the linked diagram also involved in active state agonist binding? Or are they completely different? If the latter is true, does this suggest an endogenous CB1 antagonist which enables more precise neuron signalling?
 
All those double bonds mean it's not very stable compared to some other compounds, actually - they are all places for oxidation to happen, or rearrangement to a trans- double bond. And the amide on the end tends to get hydrolysed in biological environments.

Besides all that, I don't know how potent it would be... oleamide is a structurally related compound that is a CB1 agonist but I've never heard of it being used on its own as an intoxicant.

Unsaturated fatty acids have plenty double bonds as well, but they're usually fine as far as biological degradation goes, no? Although there's definitely a lot more potential for oxidation/peroxidation with double bonds.

I've tried oleamide up to 500 mg per dose. Did jack shit.
 
I'm pretty sure the answer is 8 but it's been so long since I've studied this. How many stereoisomers does quinine have?

220px-Quinine.svg.png


I count 3 stereocenters so to 2 to the 3rd power is eight, but I can't tell if some of them are the same isomer.

Also, if one drinks a liter of tonic water, how much quinidine will he be ingesting? Quinidine is an antiarrhythmic drug that is one of the stereoisomers of quinine.
 
off topic, but something funny about tonic water... tonic water was used by european settlers in africa as a way to prevent getting malaria... the drink gin & tonic came about because tonic water tasted so bad that they mixed it with gin to make it taste better.

they mixed it with gin to make it taste better

that always blew my mind lol. modern tonic water has very little quinidine compared to the stuff they used back then tho, and to answer your question, i think most tonic water manufacturers are pretty open about the amount of quinidine in their product.
 
Say the manufacturer claims 80 mg of quinine per liter. How much quinidine is that? Is it 10 mg, or is quinidine a diastereomer of quinine (20 mg, 40 mg)?

As an antiarrhythmic this is a moot point because the effective dose is in the hundreds of milligrams. But as a cytochrome inhibitor, quinidine is efficacious even at 10 mg.
 
Tonic water contains quinine, not quinidine, although presumably "olde fashioned" tonic water was both, extracted from whatever bark...
 
^thank you. I had thought that "quinine" referred to the racemic mixture.
 
Can the tropane ring undergo inversion?

In other words, is (2R)-2-carbomethoxytropinone the same as (4R)-4-carbomethoxytropinone?

Opsin draws it badly but oh well:

(2R)-2-carbomethoxy-3-oxo-tropane.png


(4R)-4-carbomethoxy-3-oxo-tropane.png


My gut instinct is that ring inversion can't take place to a great degree, and if it does take place, it does so at a much slower conversion rate than say cyclohexane
 
Not easily, no. I'd imagine the etheno bridge would lock the ring.
 
transition state energy too high! need C-C or C-N bond breaking.. unless you have catalyst to stabilized TS
 
Besides all that, I don't know how potent it would be... oleamide is a structurally related compound that is a CB1 agonist but I've never heard of it being used on its own as an intoxicant.

Oleamide is found in (former) spice synthcan blend of ancient time (during the boom of JWH-018 and -081 era long ago), in massive amount. But i don't believe it has central effect via smoking, too large molecule to vaporize and too easy to go thermal oxidation while heating.
There have been anecdotes of people trying oral oleamide (on different occasion, and 3-4 different group of people) without any central effect. Some reported slight nausea (i think its maybe the smell/fatty texture if oleamide itself) or slight 'calm' effect (maybe placebo).

Pomzazed, could you expand in more detail on the SAR of CB1 ligands. More importantly, what is required for antagonist activity.
Check your pm.
 
Some electron microscopic synaptic love for you all. Rotten membrane preservation to preserve epitopes for immunogold, but it is what it is.

Electron_microscopic_love.png
 
This is 1 smart group of mofos.

I just wanted to see if my use of ketamine might cause mental impairment but I think trying to understand this thread might be causing brain damage. I'm just sayin'.
 
Some electron microscopic synaptic love for you all. Rotten membrane preservation to preserve epitopes for immunogold, but it is what it is.

Electron_microscopic_love.png
It doesn't take much brain power to feel this image, regardless of damage from ketamine or this thread, lol..
 
Can anyone explain why there are no RC drugs similar made as esters from known drugs? Couldn´t you put practically on every drug that has either a free NH² or OH unit an ester of some form?
I know that some drugs are then simply hydrolized to release the components and others gain own medical effects in the ester form.

For example If one would take Morphine and esterfy it with GABA or Menthol, wouldn´t those molecules just hydrolize and according to the ratio you would just have to take a bit more? There are also things like Benzphetamine which is simply a Benzyl-ester of amphetamine with similar effects. The only downside I could imagine would be the "slow release" of effects, but for drugs like Oxycodone or Fentanyl this would´nt be that bad I think?

2m5lwhni.png
 
Can anyone explain why there are no RC drugs similar made as esters from known drugs? Couldn´t you put practically on every drug that has either a free NH² or OH unit an ester of some form?
I know that some drugs are then simply hydrolized to release the components and others gain own medical effects in the ester form.

For example If one would take Morphine and esterfy it with GABA or Menthol, wouldn´t those molecules just hydrolize and according to the ratio you would just have to take a bit more? There are also things like Benzphetamine which is simply a Benzyl-ester of amphetamine with similar effects. The only downside I could imagine would be the "slow release" of effects, but for drugs like Oxycodone or Fentanyl this would´nt be that bad I think?

2m5lwhni.png

Some drugs are formulated as esters and they result in time-release formulations. They often also improve oral bioavailability and (for neuroactive drugs) BBB penetration.

https://en.wikipedia.org/wiki/BL-1020

The last molecule you displayed is an ether, not an ester, so esterases cannot separate the 2 molecules. The P450 system probably wouldn't be able to either.
 
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