and the other substances Hong's group have been testing at such low concentrations is a total mystery to me. I am not aware of any precedent for the known opioid receptors one would expect to be involved to be responsive to any drug or natural ligand in the femtomolar concentration range. This is thousands of times lower than observed with other opioid effects.

They have clearly demonstrated that the critical enzyme that is inhibited is the NADPH oxidase of microglial cells. This is a complex intracellular enzyme which uses a one-electron transfer to molecular oxygen to generate the superoxide ions released when lipopolysaccharide (LPS) activates the process through a cell-surface LPS receptor. This system is part of the intrinsic immune system in the brain which serves to kill invading microorganisms that have LPS in the structure of their cell wall.

Somehow, these femtomolar-effective molecules are interfering with this process. Invoking an ordinary ligand-receptor equilibrium to achieve this at such low concentrations makes a physical chemist squirm and a medicinal chemist start thinking "homeopathy." The apparent dissociation energy in such a reaction is more typical of a stable covalent bond.

I would be interested to see if the activity of the enzyme in these microglial cell cultures returns after medium containing the drug was replaced with drug-free medium. I may give the good doctor a call on that next week!

Sorry to bore you folks with this, but writing it out it has helped me to see this phenomenon from a different angle.

Robert