The Half Decent Pharmaceutical Chemistry Blog

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.