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From what little research I've done, it appears that a significant portion of modern psychoactive drugs are fluorinated in one way or another (for example, Buproprion, Fluvoxamine, or any number of other antidepressants).

What is the motivation behind the addition of these groups? My initial guess would be that it either increases blood-brain barrier clearance or reduces the drug's metabolism, but I've been unable to find papers supporting either idea (or papers on the subject at all, for that matter). Any books/papers illuminating the subject would be greatly appreciated.

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Fluorine has a combination of unique chemical properties, which makes it very useful in drug design :

  • It is small, such that replacing a C-H with a C-F is often possible, from a sterical point of view. Halogens, which share some of the other desirable properties of fluorine, are much larger.

  • It is very electronegative: it will attract electrons strongly, which allow polarising, stabilising or destabilising various moieties.

  • It is not found in natural products (except for trifluoroacetic acid), which means our metabolising apparatus, result of evolution by exposure to such products, can have difficulty dealing with it: thus ut makes drugs more resistant to degradation.

With these properties, you either start with fluorine in mind, to make molecules that mimics transition state of reactions involving non-fluorinated compounds (thus, enzyme inhibitors), or mimic the peptide bond (but not cleavable as easily); or you add it later to a compound that already work for additional activity, or less clearance.

There are many good books and reviews, but you could start with this one.

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