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Laser-pulse technique could aid drug design

r time frames," he says. One way to beat the clock and test the Effects of a potential therapeutic agent is to present the compound as a "caged neurotransmitter," a specially constructed molecule that has no effect on receptor proteins so it can be mixed with a cell without triggering reactions.

Once the caged neurotransmitter is in place, according to Hess, a single pulse of laser light can cleave the protective cage within microseconds, allowing the neurotransmitter to bind to receptors. Then, as the freshly exposed neurotransmitter opens transmembrane channels through which electrical currents flow, investigators can watch the millisecond shifts -- between open and closed states of channels -- and determine whether a drug, such as a cocaine analog, is having the desired effect.

In the case of GEFS epilepsy, a genetic mutation is believed to be responsible for a single, inappropriate amino acid in the so-called GABA receptor in brain cells. (The disorder is called febrile because, out of the approximately 5 percent of young children who experience seizures during a high fever, a small proportion with a genetic predisposition later develop epilepsy.) Using laser-pulse photolysis, Hess and his students discovered the reason for the receptor malfunction: a shift in the equilibrium from the open-channel form toward the closed-channel form. They also tested several compounds with high molecular weights that can shift the channel-opening equilibrium -- an encouraging indication that small-molecule drugs can be found to overcome mutations in the GABA receptor and halt the raging "electrical storms" that characterize epilepsy.

Also valuable would be a treatment to short-circuit the electro-chemical effects of cocaine, Hess says. "There are more than 5 million cocaine users in the United States alone, at an estimated cost to society of $37 billion annually," he notes, citing a 1999 report by the U.S. Office of National Drug Control Policy. "During the
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Contact: Roger Segelken
hrs2@cornell.edu
607-255-9736
Cornell University News Service
15-Feb-2003


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