Chemiotics: Do you know where your drug is (and what it is doing)?

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Reading the biomedical literature is like reading a large Russian novel with thousands of characters who interact in unexpected ways. A recent paper [Nature Medicine vol. 14 pp. 382 -391 (2008)] brings together 3 such actors — CFTR, the protein mutated in cystic fibrosis, ceramide, a molecule only of interest to neurologists until recently, and amitriptyline, a drug for depression whose mechanism of action was (seemingly) known.

Let’s start with CFTR, a huge protein (1480 amino acids). CFTR mutations cause cystic fibrosis, the commonest hereditary disease of Caucasians. There must be some selective advantage to CFTR mutations as over 600 were known as of 2003. However just one accounts for >50% of all cases. It is a deletion of phenylalanine at position #508 (showing just how delicate protein structure and function really is). One guess is that the mutants protect against intestinal pathogens (infantile diarrhea kills many children in the developing world).

Ceramide and its derivatives contain two saturated unbranched hydrocarbon chains (16–20 carbons long). They are found in myelin (the wrapping of nerve fibers) which is mostly lipid. All sorts of awful hereditary neurological diseases (usually affecting children, but fortunately rare) are caused by the accumulation of molecules containing ceramide. In recent years, ceramide’s effects on non-neuronal cell proliferation and/or cell death have become prominent. Ceramide is a second messenger. The intracellular effects of ceramide in the normal workings of the brain haven’t been much studied.

Amitriptyline (Elavil) was one of the earliest antidepressants. We all knew how it worked; by blocking the re-uptake of neurotransmitters such as serotonin and norepinephrine from the synapse (except that this is an acute effect and this class of drugs — the tricyclic antidepressants — takes a few weeks to work).

Surely you see how all this fits together at this point. No? I didn’t either. Read on…

It turns out that CFTR mutations increase the levels of ceramide inside the lungs (the primary site of infection in cystic fibrosis). This is caused by alkalinization of the intracellular sites where ceramide is broken down. Elevated ceramide levels are thought to increase cell death, resulting in lung infection (the bacteria have more to munch on).

Where does amitriptyline fit in? It lowers lung ceramide levels. How? By decreasing the amount and/or the activity of an enzyme (acid sphingomyelinase) which breaks down a precursor of ceramide. The paper is silent on the mechanism(s) by which this happens (but does give two references #24, #25). Treating transgenic mice with mutant CFTR with amitriptyline decreases the frequency and severity of their lung infections. Amazing.

Where does the effect of amitriptyline on neurotransmitter re-uptake fit into all of this? It doesn’t, and that’s just the point.

Nowadays, medicinal chemists design organic molecules to fit into slots of proteins whose function they are trying to alter. The tricyclic antidepressants weren’t discovered this way (they are much older), but papers like Mol. Pharmacol. vol. 50 pp. 957–965 (1996) found crucial amino acids in the re-uptake protein to which they bound. A fairly open and shut case for their mechanism of action.

Except it isn’t. Who knows how many designer drugs are really working the way we think they do. A cautionary tale indeed…

Go to the profile of Stu Cantrill

Stu Cantrill

Chief Editor, Nature Chemistry, Springer Nature

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