Wednesday, May 9, 2012

Metformin for treating blindness

I found this nice example for polypharmacology on Science Blog about a new indication of metformin.

Here is metformin:

The story in a nutshell:

"University of Texas Medical Branch at Galveston researchers have discovered that ... metformin, which is commonly used to control blood sugar levels in type 2 diabetes, also substantially reduced the effects of uveitis, an inflammation of the tissues just below the outer surface of the eyeball. Uveitis causes 10 to 15 percent of all cases of blindness in the United States. The only treatment now available for the disorder is steroid therapy, which has serious side effects and cannot be used long-term."

I found an ancient article suggesting that metformin acts as a weak histamine agonist, but only histamine H1 and H2 receptors were available at that time. This paper shows that metformin can increase gastric acid levels which is probably associated with a weak H2 stimulation. It would be interesting to see if metformin has got a significant level of H4 affinity. Since H4 antagonism has been shown to reduce inflammation, H4 affinity of metformin might be the missing link here.

In fact, we and others have already found several guanidine containing H4 ligands, see some examples here:

This compound was found by our large-scale structure-based H4 screen.

This is agmatine, published as a low affinity H4 ligand in this paper.

This is VUF8430, another H4 ligand published in this paper.

Anyone interested in measuring the H4 affinity of metformin? :)

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