March 2013 – Page 2

03.26.2013

lithium and bipolar

Lithium has been used for over 60 years as a treatment for manic depressive or bipolar disorder. The treatment is one of the most effective for the disorder as well as one of the most inexpensive. Bethany Halford surveys the current research on the drugs mechanism of action in this week’s C&EN:

Lithium has a reputation for being moderately effective at treating or preventing bipolar depression. Scientists know that lithium displaces magnesium ions and inhibits at least 10 cellular targets. They have been able to narrow that range on the basis of what lithium inhibits at therapeutically relevant concentrations, roughly 0.6 to 1 mM.

One putative lithium target researchers have been pursuing for decades is inositol monophosphatase, or IMPase. The enzyme is part of the phosphatidylinositol signaling pathway. It strips the phosphate off of inositol phosphate to produce inositol, a key substance in the biosynthesis of compounds that trigger cellular responses.

There is some evidence that in bipolar patients the phosphatidylinositol signaling pathway becomes hyperactive. Inhibiting IMPase halts the pathway and depletes inositol. Adding credence to this theory, researchers have fingered inositol depletion in the mechanisms of two other bipolar medications—carbamazepine (Tegretol) and divalproex (Depakote), also called valproic acid.

Click the link for much much more.

03.22.2013

a death receptor crystal structure

Illustrations of the binding pockets of 5-HT1B and 5-HT2b Serotonin receptors. Image from Science via C&EN.

Receptors for the neurotransmitter serotonin are popular drug targets. Drugs that target these receptors are used to treat problems like depression and migraine headaches. Serotonin receptors are also the targets of some psychedelic drugs like LSD and mescaline.

There are at least 14 subtypes of serotonin receptors known. Most of the drugs that target one subtype of serotonin receptor will also target the others. This is usually not a problem except in the case of one type called 5-HT2B. This receptor is called the death receptor because activating it can cause heart problems that will lead to death. This receptor is to be avoided.

Chemical & Engineering News brings word of two crystal structures that might help drug developers better avoid activating the 5-HT2B subtype of receptors:

Help will come from new crystal structures of 5-HT_1B and of 5-HT_2B, each bound to the migraine drugs ergotamine and dihydroergotamine (Science,DOI: 10.1126/science.1232807 and DOI: 10.1126/science.1232808). The findings provide a blueprint for designing more selective 5-HT inhibitors.

The team behind the structures includes Raymond C. Stevens, a chemistry and molecular biology professor at Scripps Research Institute, La Jolla, Calif.; Bryan L. Roth, a pharmacology professor at the University of North Carolina; H. Eric Xu, director of the Center for Structural Biology & Drug Discovery at Van Andel Research Institute in Grand Rapids, Mich., and Hualiang Jiang, a professor at the Shanghai Institute of Materia Medica.

This is major news for our field,” adds Kathryn A. Cunningham, a professor in the pharmacology and toxicology department at the University of Texas Medical Branch. “The structures were solved for the receptor-ligand cocrystals, which provides important insights into how the receptors work.”

The importance of selectivity was most infamously illustrated in the 1990s by the obesity treatment Fen-Phen (fenfluramine-phentermine). Both molecules targeted 5-HT receptors, but they weren’t selective enough. Unbeknown to scientists, they also bound to the death receptor, 5-HT2B, triggering sometimes-fatal cardiovascular side-effects. Fen-Phen’s withdrawal from the market was the largest in history and cost its manufacturer, Wyeth, billions of dollars in damages.

Check out the original research here and here.

03.21.2013

the eerie genetic similarity of giant squid

Giant Squid

The giant squid is one of Nature’s most elusive animals. In fact, the first video of the animal in it’s natural habitat was only captured this January. Now a new study of the DNA in squids from around the world shows that they are all the same species. The study appears in PNAS. It looks at the DNA from dead squid that had washed ashore around the world and compared the sequences. It turns out that they are all eerily similar. The species has very little genetic diversity. From Scientific American:

When the researchers looked closely at the mitochondrial DNA of the creatures, they noticed something remarkable. Irrespective of where they came from — be it be it California, Japan, South Africa, New Zealand or somewhere else — the squid were genetically very similar.

In fact, the diversity of Architeuthis is lower than that for any other marine animal, except one — the basking shark Cetorhinus maximus, whose current population is thought to have rebounded from a small number of individuals. At first, says Thomas Gilbert, a geneticist at the University of Copenhagen and an author of the study, “When we found that the global genetic diversity of the giant squid was this low, we figured we had made an error.” But then the team checked their numbers again and saw that they were correct.

The findings not only make it clear that all giant squid around the world are the same species, but they also hint that, like the basking shark, the animals came close to extinction at some point in the not too distant past. The results are published inProceedings of the Royal Society B.

GOLLYGEE!

Month: March 2013 (page 2 of 8)

lithium and bipolar

a death receptor crystal structure

the eerie genetic similarity of giant squid