Abstract
The lack of predictive in vitro models for behavioral phenotypes impedes rapid advancement in neuropharmacology and psychopharmacology. In vivo behavioral assays are more predictive of activity in human disorders, but such assays are often highly resource-intensive. Here we describe the successful application of a computer vision-enabled system to identify potential neuropharmacological activity of two new mechanisms. The analytical system was trained using multiple drugs that are used clinically to treat depression, schizophrenia, anxiety, and other psychiatric or behavioral disorders. During blinded testing the PDE10 inhibitor TP-10 produced a signature of activity suggesting potential antipsychotic activity. This finding is consistent with TP-10’s activity in multiple rodent models that is similar to that of clinically used antipsychotic drugs. The CK1ε inhibitor PF-670462 produced a signature consistent with anxiolytic activity and, at the highest dose tested, behavioral effects similar to that of opiate analgesics. Neither TP-10 nor PF-670462 was included in the training set. Thus, computer vision-based behavioral analysis can facilitate drug discovery by identifying neuropharmacological effects of compounds acting through new mechanisms.
Highlights
Pharmaceutical companies and many academic centers have thousands of high-quality compounds that represent potential new drugs
Our work demonstrates the usefulness of a computer vision-based system for identifying behavioral effects of novel compounds and mechanisms in a relatively high-throughput in vivo assay
The PDE10A inhibitor TP-10 demonstrated a behavioral signature in the PGI Analytical System that was more similar to that of known antipsychotics than to that of other classes of neuropharmacological agents
Summary
Pharmaceutical companies and many academic centers have thousands of high-quality compounds that represent potential new drugs These high-quality compound collections contain thoroughly studied development candidates and, in many cases, “old” drugs that were generated for non-CNS disorders but that might be useful therapies for one or more psychiatric diseases. Testing these compounds for activity relevant to treating psychiatric diseases is challenging. Because psychiatric diseases generally result from disorders of cell–cell communication or circuitry, intact systems are required to detect improvement in disease-relevant endpoints These endpoints are typically behavioral in nature, often requiring human observation and interpretation
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