Methylgloxal and anxiety disorder

methylglyoxal, aka pryuvaldehyde

A recent paper in The Journal of Clinical Investigation by researchers from the University of Chicago, working together with Assistant Research Professor of Biochemistry Leigh Plant from Brandeis, reveals a new mechanism for anxiety disorders involving the metabolite methylglyoxal (MG) (right).  The researchers investigated the effect of Glyoxalase 1 (Glo1) expression in mice. Increasing Glo1 copy number, and hence expression, in mice increased anxiety-like behavior. Since Glo1 metabolizes MG, they looked for a direct effect by administering MG, and found it had an anxiolytic effect in the mouse model (n.b.. MG is toxic, so don’t take it to treat anxiety). Inhibitors of Glo1 might therefore have anxiolytic effects, which they showed for the inhibitor S-bromobenzylglutathione cyclopentyl diester

Electrophysiology experiments were conducted to elucidate the mechanism of action of MG, suggesting that it had a GABAergic effect in vivo, and specifically that it is an agonist of the GABAA receptor in multiple neuron types.

So why is a relatively reactive small molecule, normally considered a by-product of glycolysis in animals, acting at neuronal receptors? Can this be exploited with pharmacological methods? What other functions does methylglyoxal have in the nervous system?  It may have many — another very recent paper in Nature Medicine suggests a role for MG in pain sensitivity and diabetic neuropathy, so there may be many interesting parts to this story.

Pre-med undergraduates should take note — keeping track of all those metabolites in glycolysis that you learn about in introductory biochemistry is far from irrelevant to modern medicine!



Phantasmidine, a Nicotinic Receptor Agonist from Ecuadoran Poison Frogs

IIn 1992, the lab of the late John Daly at NIH reported the isolation of epibatidine (1) from the skin of an Ecuadorian poison frog.  In addition to being a toxin, epibatidine has potent analgesic activity. Subsequent studies showed that this activity resulted from interaction with acetylcholine nicotinic receptors (nAChRs) with binding to some of the receptors at sub nanomolar levels.  The binding to several different types of nAChRs may be responsible for its non-selective activity.

In 2010, the Daly group reported the isolation and tentative structure determination of the epibatidine congener phantasmidine (2) from a total sample of only 20 micrograms. Preliminary biological studies with the limited material available indicated that phantasmidine (2) differs from epibatidine (1) by being selective for β4-containing nicotinic receptors, suggesting that phantasmidine might fill a niche for characterization of these receptors. However, the limited natural material available precluded detailed pharmacological analysis and definitive structure determination.

In their recent paper in Organic Letters entitled the Synthesis of Phantasmidine, the Snider lab at Brandeis reported a short and efficient synthesis of phantasmidine that confirmed the tentative structure and makes ample material readily available for further biological evaluation, which is currently in progress.  To prepare the tetracyclic framework, they invented a new tandem intramolecular aldol reaction-nucleophilic aromatic substitution reaction to form both five membered rings in a single reaction.   Treatment of keto amide 3 with sodium hydroxide gave aldol adduct 4 which cyclized to lactam 5.  Reduction of the lactam completed a practical synthesis of phantasmidine (2).

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