Saturday Night Synthesis: Methoctramine
Good evening and welcome to this very special episode of Saturday Night Synthesis! For the grand finale of the first series we have invited a great guest, tonight.
This molecule is not even a proper drug, but is likely to be the coolest I've EVER described. It was, in fact, designed by the Head of the Department of Pharmaceutical Chemistry of my university, the same man who lectured me on my last course of pharmaceutical chemistry.
This has some consequences: I have the opportunity to describe every detail of tonight's prep and how this molecule was designed.
I begin with the latter. Here is the aim: to find an M2 receptor antagonist with the highest selectivity.
This was their starting point. It's called benextramine, it's an irreversible alpha-1 antagonist: its four amino groups are all protonated at physiologic pH and, through an induced fit mechanism, force the receptor to expose four cysteines, which react with the disulfide, binding covalently.
Now, that's fine, but researchers realised this molecule has competitive antagonism on muscaric receptors as well.
So, they threw away most of the functional groups and reduced everything to a polyamine.
Such a simple backbone is what they later called the (perfect) universal template: theoretically, it could react with any receptor, it actually has specific carriers, all the amines are protonated (only if n > 3, though) so that they could react with carboxyls, hydroxyls, thiols and aromatics.
What's more, the structure is extremely flexible and easy to modify, so it is NOT a toxin.
You can, in fact, vary the distance between the amines and/or add functions to achieve selectivity.
So, there you are: a pretty easy operation. They came up with a simple polyamine, as a base, and turn it into this!
It's called, simply, Methoctramine and I'm glad to report that it's just uncanny.
Its structure can remind you of benextramine but the disulfide bond is gone, so there's no risk of covalent bonds any more.
The result is dramatic. It's, almost equally, incredibly selective for either M2 and M4 receptors and the pA2 is just astonishing: 7.52 on guinea-pig atria (M2).
To sum up, it's not a drug, but a glimpse into the future of M2-selective drugs.
And now, let the synthesis begin!
First of all, if you, too, can't see almost anything of what's written on the arrows, here is a bigger picture.
The first two reagents are rather simple: a diamine and the product of a banal reaction between aminocaproic acid and benzyloxycarbonyl chloride. The ratio is 1:2.
For this first step, we must use dioxane as solvent of either the salification of the acid and its actvation (through an anhydride).
The amide will be easily yielded, thanks to the fact that ethanol and CO2 are released.
Then, the carbamate is removed: my professor said at this point you can't opt for hydrogenolysis, because the adduct isn't soluble in the solvent we should use.
So, they chose HBr in acetic acid.
Moving on, prolonged extraction is needed to achieve a decent final yield. After that, we yield an aromatic Schiff base, which is stabilized by resonance.
Once the said Shiff base has been treated with sodium borohydride, the amide is reduced with borane, at 110*C, in diglyme.
What a massive synthesis, isn't it?
So, that's it for this series: SNS will be back next October.
Meanwhile, I hope you will enjoy my other posts as well: don't worry, pharma chem freaks, because there will always be room for such an important subject here!
