Wednesday, April 15, 2009

Fluorescent anesthetic compound – a new avenues for drug discovery?

We did know about the fluorescent biomarkers in drug discovery, especially to establish the mode of action of drugs. But this is something really interesting by using the fluorescing compound 1-aminoanthracene, (1-AMA), the team developed a high-throughput assay to test for the anesthetic activity.

This research is of great importance because of the fact that one can search for new anesthetic drugs and also new molecular targets with help of high resolution images of the compounds in action. As the compound is fluorescent, researchers will be able to image the compound in vivo (to study its physiological effects). Also one can assess the mode of action and know the concentrations (dose required) of anesthetic administration. Hope this will go a long way in the history of drug discovery, as one can improve the efficacy with reduced side effects.

Researchers confirmed the compound 1-AMA, as anesthetic after testing it successfully in tadpoles. By using transparent, albino tadpoles in the study, researchers were able to follow the fluorophore tag and image it in the brain of the immobilized, living animal.

The following is the explanation of the research group :

Researchers noticed a resemblance in the crystal structure of the apoferritin protein to that of the transmembrane region of the superfamily of ligand-gated channels that includes the GABA receptor. Anesthetics are known to positively modulate GABA signaling.

Because 1-AMA competes with other anesthetics to bind to apoferritin, researchers surmised that the protein likely binds to the same region of apoferritin as traditional anesthetics and thus shares their mechanism of action. Fluorescence of 1-AMA is enhanced when bound to apoferritin. Thus, displacement of 1-AMA by other anesthetics attenuates the fluorescence signal and allows determination of anesthetic affinity, that is, the drugs that bind tightly to the ferritin anesthetic site. In this way, 1-AMA fluorescence could be used to discover new anesthetics. This provides a unique fluorescence assay for compound screening and anesthetic discovery.

Using confocal microscopy to image the distribution of the protein, the team found that 1-AMA localizes largely in the brain and olfactory regions, unlike some general anesthetics which spread widely throughout the body. Ideally, clinical anesthetics would have a very focused target area in order to minimize systemic toxicity.

Though further studies are essential it’s a good beginning congrats Ivan J. Dmochowski and his group for this achievement.

As we know that, anesthetics bind weakly to their chemical targets and there by leading to some unintended side effects and hence searching for new targets in the central nervous system is difficult. But now with this technique, one can search for other compounds. Like what they have achieved.

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