title: In Vivo Systems Response Profiling and Multivariate Classification of CNS Active Compounds: A Structured Tool for CNS Drug Discovery.
abstract: This paper describes the application of in vivo systems response profiling in CNS drug discovery by a process referred to as the Integrative Screening Process. The biological response profile, treated as an array, is used as major outcome for selection of candidate drugs. Dose-response data, including ex vivo brain monoaminergic biomarkers and behavioral descriptors, are systematically collected and analyzed by principal component analysis (PCA) and partial least-squares (PLS) regression, yielding multivariate characterization across compounds. The approach is exemplified by assessing a new class of CNS active compounds, the dopidines, compared to other monoamine modulating compounds including antipsychotics, antidepressants, and procognitive agents. Dopidines display a distinct phenotypic profile which has prompted extensive further preclinical and clinical investigations. In summary, in vivo profiles of CNS compounds are mapped, based on dose response studies in the rat. Applying a systematic and standardized work-flow, a database of in vivo systems response profiles is compiled, enabling comparisons and classification. This creates a framework for translational mapping, a crucial component in CNS drug discovery.
authors.affiliation: Department of Pharmacology, Gothenburg University , SE-405 30 Gothenburg, Sweden.|Integrative Research Laboratories Sweden AB , Gothenburg SE-413 46, Sweden.
authors.forename: Susanna
authors.identifier: 0000-0002-8688-880X
authors.initials: S
authors.lastname: Waters
authors.affiliation: Integrative Research Laboratories Sweden AB , Gothenburg SE-413 46, Sweden.
authors.forename: Peder
authors.initials: P
authors.lastname: Svensson
authors.affiliation: Integrative Research Laboratories Sweden AB , Gothenburg SE-413 46, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Kullingsjö
authors.affiliation: Department of Pharmacology, Gothenburg University , SE-405 30 Gothenburg, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Pontén
authors.affiliation: AstraZeneca R&D , SE-431 83 Mölndal, Sweden.
authors.forename: Theresa
authors.initials: T
authors.lastname: Andreasson
authors.affiliation: AstraZeneca R&D , SE-431 83 Mölndal, Sweden.
authors.forename: Ylva
authors.initials: Y
authors.lastname: Sunesson
authors.affiliation: Integrative Research Laboratories Sweden AB , Gothenburg SE-413 46, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ljung
authors.affiliation: Integrative Research Laboratories Sweden AB , Gothenburg SE-413 46, Sweden.
authors.forename: Clas
authors.initials: C
authors.lastname: Sonesson
authors.affiliation: Integrative Research Laboratories Sweden AB , Gothenburg SE-413 46, Sweden.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Waters
mesh_terms: D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D016018:Least-Squares Analysis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002491:Central Nervous System Agents
keywords: Neurochemistry; antipsychotics; biomarkers; dopidines; drug discovery; monoamines; multivariate data analysis; phenotypic screening; response profiles; rodent behavior; systems pharmacology; translational modeling