Where are the new drugs?  pg. 3

Because loss of dopamine disrupts a complex web of signaling pathways in the brain, it may be possible to restore this balance by “tweaking” pathways involving other neurotransmitters.

While at Merck Research Laboratories, where he was head of neuroscience, Conn and his colleagues found that activating a particular GPCR that bines the neurotransmitter glutamate—mGluR4—relieved symptoms of Parkinson’s disease in animals. However, they could not find a compound that binds only to mGluR4, and does not activate other glutamate receptors elsewhere in the brain.

Allosteric modulation might solve the problem.

This tongue twister refers to the ability of some compounds to bind to a secondary site on a receptor in a way that “modulates” its activation by a primary “ligand” such as a neurotransmitter or hormone. Primary ligands fit into the receptor’s main binding site like a key fitting a lock, and “turn it on.”

The modulator, on the other hand, acts like the dimmer switch in an electrical circuit, adjusting the intensity of the receptor’s activation. The anti-anxiety drugs Valium, Xanax, Librium and Ativan, for example, “potentiate” or turn up the activity of the benzodiazepine receptor when it binds to its primary ligand, the neurotransmitter gamma-aminobutyric acid (GABA).

Conn wondered whether he could find an allosteric potentiator that was specific for mGluR4. However, “my department could only handle a maximum of three programs at any given time,” he says. “And to take a kind of half-baked idea… and decide we’re going to really pull the trigger on a drug discovery program was such a high risk.”

Then, in 2003, he saw an opportunity to pursue his idea at Vanderbilt.

A generation ago, Conn might have spent his entire career searching for a compound that could modulate mGluR4 activity. Now, thanks to Vanderbilt’s high-throughput screening facility, he and his colleagues can test tens of thousands of small molecules for drug-like activity in a single day.

Ultra low volume liquid handlers squirt nanoliter amounts of the compounds into 384-well “microplates” containing their target. Reactions are detected via fluorescence or luminescence as the plates are maneuvered by articulated robots through the screening system.

Compounds that bind to the allosteric site on mGluR4 will be tested in animal models of Parkinson’s disease to see if they actually relieve muscle rigidity and restore coordination.

Conn admits that there is considerable skepticism among his colleagues in industry about “whether we can really pull it off.” But that hasn’t discouraged universities across the country from developing similar capabilities for screening compounds.

Three-dimensional crystal structure of a G protein coupled receptor (GPCR) embedded in a cell membrane, with its loosely attached heterotrimeric G protein, consisting of alpha, beta and gamma subunits, inside the cell. When a ligand, such as a neurotransmitter or hormone, binds to its GPCR, the receptor changes shape in a way that catalyzes the release of guanosine diphosphate (GDP) from the alpha subunit. GDP, an organic molecule involved in intracellular energy exchange, is replaced by the higherenergy guanine triphosphate (GTP). That, in turn, causes the alpha subunit to break apart from the beta and gamma subunits. The subunits then interact with other intracellular proteins to transmit signals down two independent pathways. Within a few seconds, GTP is converted back to GDP, the subunits recombine, and the signals are "turned off."
Illustration by William Oldham
“This is where we fill the gap,” he explains. “I think we are at a turning point in the whole drug discovery industry… We are at a point where different players in the whole therapeutic discovery arena can start to bring a lot more to bear to this process…

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