Dec 16 2010
The Scripps Research Institute and the University of California, San Diego, (UCSD) School of Medicine have been awarded approximately $7.5 million over five years to develop novel compounds that could eventually become drug candidates for the treatment of nicotine dependence, and possibly other drug addictions. Of the funds awarded, $5 million will go to Scripps Research, $2.5 million to UCSD.
The grant from the National Institutes of Health (NIH) will fund research focused on finding novel positive modulators for GABAB receptors that have the potential to become treatments for nicotine addiction. GABAB receptors, found in the central nervous system, mediate some of the actions of GABA, the major inhibitory neurotransmitter in the brain involved in regulating several brain functions, including reward signals that play a role in drug addiction.
Consortium principal investigators are Patrick R. Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute on the Jupiter, Florida campus of Scripps Research; M.G. Finn, a professor in the Department of Chemistry and the Skaggs Institute for Chemical Biology on the La Jolla, California campus of Scripps Research; and consortium director Athina Markou, a professor in the Department of Psychiatry at UCSD and adjunct professor in the Scripps Research Molecular and Integrative Neurosciences Department (MIND).
"We're looking for small molecules that will affect very complex feedback mechanisms in the brain, but in a subtle way," Finn said of the new project. "While the field has focused on some obvious receptor pathways in the brain, these are involved in many different functions and side effects are impossible to avoid. Positive modulation of GABAB receptors - if we can find the right agent - has strong potential to help people resist the addiction impulse without messing with the main circuitry of the brain."
This consortium grant is a competitive renewal of a previous award to Markou, in collaboration with Novartis, when her laboratory was located at Scripps Research. Chemists at Novartis involved in the previous phase of the program discovered a number of small-molecule modulators of the GABAB receptor. Further study resulted in the development of the first highly selective positive modulators for GABAB receptors. Subsequently, work in the Markou laboratory showed that these compounds had desirable effects on nicotine dependence in animal models, while offering a better side-effect profile than other alternatives under study (full agonists at the same receptors).
"As a result, a strong preclinical proof-of-concept has already been established for this novel approach to the treatment of nicotine addiction that drives the harmful tobacco smoking habit," Markou said. "The preclinical results in our animal models are really exciting and have provided the momentum for me to continue on this project, even after Novartis indicated that it no longer wished to maintain this collaboration."
Markou reached out to her Scripps Research colleagues and formed a new research team to continue work on the initiative. "I am very fortunate to have such outstanding collaborators who are cutting-edge chemists and have extensive experience in drug discovery," she said. "After the neurobiological studies pointed out the important role of the GABAB receptor in nicotine reward, and we had positive data in a variety of animal models of nicotine dependence, it was time to focus our efforts on discovery of new molecules that could become therapeutics to assist people to quit smoking."
The new funding will advance this effort.
Griffin noted, "We want to expand the pipeline of possible compounds that could be developed into potential therapies. Once we have a better mechanistic understanding of the factors that drive selective modulation of GABAB receptors, we can assess how these new compounds affect various behaviors in animal models. In the end, this approach has the best potential to provide potent innovative therapies for human nicotine addiction."
Scientists on the two Scripps Research campuses will collaborate in the design of new GABAB receptor modulators. The compounds will then be synthesized in California and tested in Jupiter. Key personnel from the Florida campus include Patricia McDonald and Michael Cameron, both assistant professors in the Department of Molecular Therapeutics. Compounds that successfully make it past several rounds of evaluation will be tested in animal models at UCSD.
"In many ways, this is the kind of collaboration that [Scripps Research President] Richard Lerner had in mind when he founded Scripps Florida," Finn said. "Jupiter is the state-of-the-art for assay development, chemical screening, and compound evaluation to support biomedical research in the country, possibly the world. And in La Jolla, we are developing some unique approaches to synthesis. It's a great match. This really is what everybody hoped would happen."
"This is not a typical individual investigator-driven science grant," Griffin said. "It's really a highly integrated and collaborative research program to discover innovative drug candidates. In this particular program to discover novel modulators of GABAB, the Scripps Florida team took on the translational role of a large pharmaceutical company. We are providing the framework and support to discover potent and functionally selective GABAB modulators that are efficacious in animal models of tobacco addiction. This project is very exciting and very energizing."
Source: Scripps Research Institute
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