Physics to the rescue

It’s enough to drive a medicinal chemist nuts. General anesthetics are an extremely wide ranging class of chemicals, ranging from Xenon (which has essentially no chemistry) to a steroid alfaxalone which has 56 carbons. How can they possibly have a similar mechanism of action? It’s long been noted that anesthetic potency is proportional to lipid solubility, so that’s at least something. Other work has noted that enantiomers of some anesthetics vary in potency implying that they are interacting with something optically active (like proteins). However, you should note sphingosine which is part of many cell membrane lipids (gangliosides, sulfatides etc. etc.) contains two optically active carbons.

A great paper [ Proc. Natl. Acad. Sci. vol. 111 pp. E3524 – E3533 ’14 ] notes that although Xenon has no chemistry it does have physics. It facilitates electron transfer between conductors. The present work does some quantum mechanical calculations purporting to show that
Xenon can extend the highest occupied molecular orbital (HOMO) of an alpha helix so as to bridge the gap to another helix.

This paper shows that Xe, SF6, NO and chloroform cause rapid increases in the electron spin content of Drosophila. The changes are reversible. Anesthetic resistant mutant strains (in what protein) show a different pattern of spin responses to anesthetic.

So they think general anesthetics might work by perturbing the electronic structure of proteins. It’s certainly a fresh idea.

What is carrying the anesthetic induced increase in spin? Speculations are bruited about. They don’t think the spin changes are due to free radicals. They favor changes in the redox state of metals. Could it be due to electrons in melanin (the prevalent stable free radical in flies). Could it be changes in spin polarization? Electrons traversing chiral materials can become spin polarized.

Why this should affect neurons isn’t known, and further speculations are given (1) electron currents in mitochondria, (2) redox reactions where electrons are used to break a disulfide bond.

The article notes that spin changes due to general anesthetics differ in anesthesia resistant fly mutants.

Fascinating paper, and Mark Twain said it the best “There is something fascinating about science. One gets such wholesale returns of conjecture out of such a trifling investment of fact.”

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