In vivo phenotypic drug discovery: applying a behavioral assay to the discovery and optimization of novel antipsychotic agentsThe authors declare no competing interests.Electronic supplementary information (ESI) available: Supplementary data associated with this article can be found in the online version. See DOI: 10.1039/c6md00128a

• Main Authors: Shao, Liming, Campbell, Una C, Fang, Q. Kevin, Powell, Noel A, Campbell, John E, Jones, Philip G, Hanania, Taleen, Alexandrov, Vadim, Morganstern, Irene, Sabath, Emily, Zhong, Hua M, Large, Thomas H, Spear, Kerry L
• Format: Journal Article
• Published: 16.06.2016
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c6md00128a

Phenotypic drug discovery (PDD) is increasingly being recognized as a viable compliment to target-based drug discovery (TDD). By measuring functional changes, typically at a systems level, PDD can facilitate the identification of compounds having a desirable pharmacology. This capability is particularly important when studying CNS diseases where drug efficacy may require modulation of multiple targets in order to overcome a robust, adaptive biological system. Here, we report the application of a mouse-based high-dimensional behavioral assay to the discovery and optimization of a structurally and mechanistically novel antipsychotic. Lead optimization focused on optimizing complex behavioral features and no explicit effort was made to identify the target (or targets) involved. A mouse-based assay (SmartCube) was used for both screening and lead optimization of a novel antipsychotic.