Neuropsychiatric disorders are complex and involve multiple neuronal circuits. It is not surprising therefore that many of the most efficacious drugs in psychiatry have exceedingly complex pharmacology and were often discovered by observing how an animal's and human's behavior were altered in response to these drugs. For this reason, we believe that, to the extent possible, animal's behavior-based drug discovery and lead optimization should provide novel avenues to the treatment of psychiatric disorders.
The aim of this proposal is a large-scale, automated in vivo screening of libraries of compounds to discover novel compounds for the treatment of psychiatric disorders. We will combine two novel technologies that have the potential to substantially change how drug discovery is carried out. PsychoGenics will utilize its proprietary, high throughput broad-based behavioral assay for mice known as SmartCube(tm) to screen and optimize compounds selected from proprietary collections of compound mixtures provided by Mixture Sciences. SmartCube is an automated test for mice that allows us to determine the antidepressant, anxiolytic and antipsychotic potential of a test compound in only one test of 90 minutes. Compounds will be initially administered as mixture instead of single chemical entity and screen for their behavioral-activity. Two mixtures containing 64,0000 thousands compounds each will be tested. These compounds will be related to a common pharmacophore, which will imply a deconvolution process to define the active compounds. Mixture Sciences' algorithms will be utilized to identify active individual compounds from the mixtures that exhibit behavioral activity in mice and we will synthesize and test these individual compounds to confirm their level of activity in vivo. At that stage, active compounds will be further tested in more traditional behavioral assays to confirm that they are true positive and to further evaluate their level of activity and spectrum of therapeutic application. We will generate data for approximately 128,000 compounds and reduce the screening time from many years to several months. From this process we hope to select at least one compound for which further pre-clinical evaluation and likely clinical development will be warranted.
| Houghten, Richard A; Pinilla, Clemencia; Giulianotti, Marc A et al. (2008) Strategies for the use of mixture-based synthetic combinatorial libraries: scaffold ranking, direct testing in vivo, and enhanced deconvolution by computational methods. J Comb Chem 10:3-19 |
