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.