The Half Decent Pharmaceutical Chemistry Blog

When it came out, the film “Wir Kinder vom Bahnhof Zoo” had a huge impact on the European audience: that crude, disillusioned and realistic portrait of a doomed and hopeless generation of Western youngsters was so impressive that the Bahnhof Zoo is still evoked every time someone refers to a particularly miserable area of a big, industrialised, Western city, where drug abuse is a dramatic issue, especially among the young generations. Personally, I find this appropriate as the images and atmospheres of that film are dramatically powerful and evocative.

I’ve quickly searched through the old posts and realised I have never mentioned or described or provided pictures of the area where my lab is located. On award-winning Carbon-based Curiosities you could read a post entitled “If you ever want to visit, this is why”, but, as you might predict for the title, this post is pretty much the opposite as the lab is right in the middle of an area (a sort of a park) where you could perfectly use as a location for a film about junkies. Or an electoral spot of a Conservative MP. I must admit, being surrounded by people sticking nails in their arms, I’ve regretted not having a vicious, old-fashioned, evil, Conservative mayor or simply lots of policemen constantly patrolling the place. Especially the day my bike was stolen. Especially when I go to the lab on Saturday afternoon and, leaving the building, you suddenly realise someone is melting skunk on tinfoil near you (although you see him from a higher and therefore protected position). Especially when your colleagues tell you last year someone stole the group leader’s laptop and mobile from his office and then (apparently the same person) returned a couple of months later to stole some wallets from the offices downstairs. Especially when you arrive in the morning and are welcomed by revolting scenes like this.

I’m not exaggerating, believe me: we are literally under siege. Frankly, this isn’t that surprising considering a few, peculiar features of the place: no CCTV, no (fake) security cameras, no lights for when it gets dark, lots of bushes and sheltered corners (like the one in the picture), which provides an ideal habitat for addicts. Although we need shelters, as these nasty people don’t care about us, unless they need money to buy junk and, therefore, steal something as we were some sort of cash machine. Every time I leave the place after 7 pm I always spot at least one person (1 out of 4 is a woman) consuming drugs. Most of the times I even found myself no more than a metre from them.

You might ask why, if this is how things are, none of us has ever called the police. Thing is junkies only come to consume and cash: they leave in the streets (near a police station and you, as well as me, might argue why they don't do something!). You might even wonder how all these people manage to get into the area. The problem is that the whole park can’t be closed because of the vast number of people working in the different buildings, who have to come and go. And, trust me, even when the entrances are both closed (at night and throughout the weekend) it is surprisingly easy to climb over the walls and get in.

I have often been on the verge of doing something: either angrily calling the police and confront them too, because of their absence at such a critical site, or reaching the second floor, where there is our tissue culture lab, take the bottle where we throw away all the waste products from cultures and, given there is a window just below a popular injection-site, pour it litres of stinky and potentially very harmful liquid over some undesired guest (I really believe I am going to try this, one day).

Meanwhile, I’ve decided to take inspiration from this appalling experience to write about another thing I’ve always meant to discuss but, oddly, never found the right pretext to do. In a nutshell, how pharmaceutical chemists design new opioids. In fact, as you may expect considering the undoubtedly positive, clinical properties of morphine, this is an important branch of this science. Nevertheless, this is a particularly complicated task too, because morphine is a complex molecule, with many features that cannot be varied at all. What’s more, of all the receptors, opioid ones are poorly understood.
The structure of morphine is impressive and certainly doesn’t look like your ideal lead. It’s actually so big, that, unlike the majority of the other quests for newer, better derivatives, chemists try to get rid of all the unnecessary bits to get to the root of the problem, identifying a basic backbone from which to start.

Morphine could be seen as the result of a piperidine, an epoxide and a phenanthrene being fused together. This molecule has five chiral centres and, so, 32 diastereoisomers of morphine could be drawn exist, although only that with configuration 5R, 6S, 9R, 13S, 14R is found in nature. Codeine and heroin are, perhaps, the best-known derivatives. As you can see, they differ only marginally from the parent compound and that’s no surprise if you think that the 3-OH is almost essential for the activity and Codeine, with a methylated hydroxyl, is, in fact, less potent. The other hydroxyl is, on the contrary, less important: oxidation or acetylation has indeed positive consequences when considering analgesic activity.
Thus, heroin is stronger than morphine because its double acetylation leads to enhanced concentration of this pro-drug at the receptor, which is located in the nervous system, through enhanced lipophilicity.
Other, less known derivatives were designed bearing in mind that the natural ligands of opioid receptor (enkephalins) have a tyrosine: so that phenol must be kept there to preserve clinical effectiveness. The amine is also fundamental and the distance between the phenol and this function has paramount importance.
However, because it was observed that the double bond and the epoxide weren’t required, the structure of morphine began to be little by little eroded from that end, yielding Levorphanol and Metazocine.
Meperidine and Fentanyl might belong to the same class of derivative but, whereas the former (on the right) is 10 times weaker than morphine, the latter, due to the more enkephalin-like benzene-amine distance, is 100 times more potent than morphine.
Finally, methadone, which seems even less similar to morphine, maintains the aromatic ring and the proper benzene-amine distance, so it’d actually be more dangerous, if it were taken parentally, but guarantees less severe withdrawal symptoms for addicts who finally decide to quit.

Take care.

Happily, my internship at the chemist’s is about to finish! Next week I’ll finally begin to work on my graduation thesis and tiding up drawers will be replaced by loading agarose gels: to state the obvious, things will improve dramatically. I’ve to make clear, once and for all, that working as a pharmacy assistant is one the most boring things I’ve ever done: you do silly preparations in a lab which looks like a kitchen when you’re lucky, because, otherwise, you spend your day taking care of the orders, putting the stuff on the shelves or in the drawers. And, even when you finally become a pharmacist, everything you studied at the university (pharmacology, for instance) is suddenly useless as you simply have to give customers what their physician prescribed and the important information you’ve to tell the patient appear on the computer as you read the barcode with your laser-pen.
Oh, and going back to the lab, as you’ll have noticed, a child would be perfectly able to make galenic preparations, given that, if the doctor didn’t write it, you’ll have to stick to some recipe with oddly no chance of bringing out your ingenuity at any time (although this might be the only improvement you experience in the transition from student/assistant to pharmacist, but it’s not needed so…).

Bored as I’ve been on this last week, I’ve literally wandered around the shop counting the days separating me from a real lab and a decent work. However, I’ve had the chance to read all the information posted for the employees and a note caught my attention: apparently, there are some forged prescriptions going around the area for a benzodiazepines called Nitrazepam, which is not available in the US, but, according to Wikipedia, is a pretty common BDZ of abuse in Sweden and England.

It shouldn’t be that difficult to realise it’s a forgery as you see it, to be honest: the name of doctor is Michele De Seenen and the patient is a bloke called Romulo Lindaoan. Obviously, if you aren’t Italian you can’t get it but let’s see if I can make everybody to understand: these names are clearly (badly) invented. Something like doctor Tom Fjbskedb and Mr. John Endjusyf (I closed my eyes and typed): totally meaningless, even if they were both immigrants from Weirdenia (and, in that case, they wouldn’t have Italian names, would they?).

Given that these prescriptions were pathetically faked, is the drug itself a forgery too? I mean: what are the features that make a benzodiazepine genuine? Well, let’s start with the BDZ backbone: this structure is the starting point for any derivative.

There are a few “minimum requirements” (as for computer programmes) which one must bear in mind: the A ring and the carbonyl must lie on the same plane and the C ring, although the benzene can be replaced by a pyridine, can’t be para-substituted (but a halogen in ortho enhances the drug).

Of course halogens bound to C7 look more familiar than the nitro-group of nitrazepam but this actually increases the affinity of the drug for the receptor: you see this benzene strengthens the binding through its pi-cloud. As a result, the more electronegative the functional group, the tighter the bond.

Other modifications that don’t interfere with the activity of a BDZ are those on the carbonyl. This function, in fact, can be turned into a 1,2,4-triazole because this wouldn’t yield steric hindrance, due to the shape of the receptor.

The N1, moreover, can undergo alkylation, but, in this case, to avoid hindrance, only small groups can be employed: a t-But would abolish any activity.
Even for the double bond C5 – N4, changes are allowed, leading to pro-drugs. 

A few months ago an Italian fashion magazine (Vogue Italia) featured a photo shoot whose title was “Cleansing. Super Mods Enter Rehab”. Inside, a group of skinny models, sorry, mods are photographed before and during their period at a rehabilitation centre. In both situations they all ware (when not naked) expensive and glamorous clothes and smoke cigarettes, which is what every super mod normally does.

One of the most popular tunes this year was sung by a skinny, tattooed British junky and alcoholic called Amy Winehouse, who endlessly repeat she won’t enter rehab (no, no, noooo!).

The point is clear: rehab has, all of a sudden, become cool. Massively cool. Unless you don’t want to look uncool, you’d better start saying things like “Oh, I’d love to come to your wedding but, you know, I’m entering rehab on Tuesday”, “You won’t believe who I sat next to in the psychologist’s lounge!”, “Some paparazzi broke in our rehab centre, as they believed Paris/Lindsey/Britney/enter the name of a celebrity who is enjoying a vacation at some exclusive clinic was there.”, etc.

And if rehab is cool, this means phenylheptylamines are glamorous, since the best-known member of this family is Mr. Detoxifier itself: methadone. So, because I aim to have a posh and fashionably blog, I am sorry for not having dedicated post to these drugs before, but it’s time to fill this gap, hoping some massive fashion magazine will notice it and decide to hire me for a report from the next Paris fashion week (September 31 - October 6).

All phenylheptylamines derive from the same, basic structure, of course.
I know what you’re thinking: “It doesn’t look like other opioid analgesics.” Well, this is not entirely correct, as you can appreciate looking at what happens when the structures of morphine and a phenylheptylamine are superimposed: not only do they share the benzene, but the tertiary amine is also present, at the same distance from the ring, in both. And notice the methyl groups, please.
Methadone is the strongest phenylheptylamine to be clinically used. As any other opioid agonist, it has analgesic properties: interestingly, its efficacy isn’t limited to opioid receptors only, but it has proved to affect monoaminergic and NMDA receptors as well. In this latter case, however, the drug acts as an antagonist, which in turn block the transmission of this system, creating such an increased analgesia that methadone is now considered the first option after an unsuccessful treatment with morphine in case of neurophatic and cancer pain.
In particular, when parentally administered, methadone is more potent than morphine. That’s why you can only administer it through oral route to mods in rehab.

Still, methadone is widely known as the treatment of choice for heroin addiction. That’s because, switching from morphine to methadone, the patient experiences weaker withdrawal symptoms (even if for longer period). The reasons for this are still to be fully understood, although there are many theories.
Methadone is not the only phenylheptylamine. At least, not the only to be designed. It remains the starting point for pharmaceutical chemists: every phenylheptylamine is derived from this molecule. That’s no surprise: it still has the best risk/benefit ratio to date and outstanding pharmacokinetics, being administrable through any route.
In fact I’m just thinking: why do we need to waste time trying to find a better one?
Well, one good reason could be that methadone therapy doesn’t always work and this not always a psychological dependence problem.

But, from now on, your answer to that question should be: “Because I want to present my new winter collection of methadone derivatives at the forthcoming fashion week in Milan!”

To help you, here is what has been tried so far. For example, moving the methyl from alpha to beta means reducing the activity and getting rid of it is a radical solution which results in an inactive compound. Interestingly the reduction of the ketone enhances the activity, especially if the alcohol is then acetylated.
You’d better keep both phenyls, but you can substitute one of them with a benzyl (as they did to yield propoxyphene) and/or look at benzene isosteric compounds. Propoxyphene is a very weak derivative of methadone, only employed in the treatment of cough, as an alternative to codeine (but you need to double the dosage…).

Last but not least, the amine. Looking at morphine, it’s no surprise that you’ll actually increase potency if you try to block it with an N,N-dimethylamine. Predictably, though, this goes with a proportioned rise of the adverse effects. Whatever group you choose for positions R3 and R4, anyway, you’ll always end up with an agonist.

There you are: now it’s your turn to design what super mods and celebrities will swallow next season.

Already?! Well, on a day like today, you can suddenly feel lonely and desperate, emotionally emptied by such a terrible thing.
So your craving worsens or, more worryingly, you realise you suffer from it, for the first time.

If you're experiencing craving for Saturday Night Synthesis, and can't wait for next October, check out this quick synthesis of one of the very first drugs designed for Parkinsonism: Trihexyphenidyl.

Old times, when pharmaceutical chemists thought you could simply treat parkinsonians with antimuscarinics!

However, if your thirst for organic chemistry can't be eased by this short prep, I'll be glad to know, next week, I'll launch a new series: Laboratoire Organique.



Even if you struggle to pronounce "adieu", you'll understand it's something dealing with organic chemistry and labs.

Although I don't want to tell you any detail, let me explain why I chose a French title for it: there are a couple of good reasons, actually.

First, I realised I don't know any French scientist writing a blog (in English), so I thought someone has to fill this void (even though just with a title).
Then, because I hope the series will be, somehow, elegant and stylish (I've no clue how I'm going to have success in this, though).

Last but not least, I've been in Paris four times (always for more than a week): I know the city very well and love it. Since last sumer I was working in Amsterdam and couldn't go there, my craving for Paris is responsible for the use of a French name.

So stay tuned, organic abusers!

Now, many people come to me and say: "Look: I had school sores, so, I took oral dicloxacillin. Now, however, I suffer from a mild urinary tract infection, for which my doctor has prescribed me cephaloxin. But I still have a lot of dicloxacillin which I wouldn't like to  throw away, wasting money! What can I do?!"

Actually, that's a lie: fortunately, no one has ever asked me such a stupid thing and now, I believe, this'll never happen, because, today, I'm going to prove how simple it is to crack antibiotics by yourself!

All you need are some banal items, you could find in every, decent, supermarket. For example, a certain quantity of 3-chloroperoxybenzoic acid is required, as you can see, right at the beginning, in order to oxidize the protected penicillin.

But, hey: can you imagine a supermarket that doesn't sell MCPBA?

Whenever I look at this reaction, Strauss' Blue Danube Waltz notes pop in my head. That's likely to be a direct consequence of my love for "2001:A space Odyssey": so, that acetate ion, which plays the key role in Morin rearrangement, always reminds me of a space shuttle, harmoniously floating.



By the way, given that the most complicated part of the job is already done, almost automatically, by the aforementioned rearrangement, the rest of the synthesis looks a little bit boring.

 

Triethylamine is added to yield the double bond.

You, then, remove the amide and the protecting group of the carboxylic function: what you get, in the end, is a close derivative of the original 7-aminocephalosporanic acid.

To increase the yield of the amide, the substituent that is added is modified so that the final step could go on smoothly: an anhydride eases the formation of the amide and the amine is efficiently protected in such a way that no interference might occur.



So, here you are: a penicillin turned into a cephalosporin through seven steps only.

Still, I believe it's not that cheaper, after all...