The NIMH Psychoactive Drug Screening Program (PDSP)

Presenter:

Jamie Driscoll
Division of Neuroscience and Basic Behavioral Science

Goal:

The goal of the NIMH PDSP is to provide the research community with access to broad screening capabilities in the form of pharmacological and functional assays. The purpose is to stimulate innovative research and development efforts in the discovery of novel tools for basic research, small molecule probes, ligands for neuroimaging, and as potential therapeutic agents for the treatment of psychiatric disorders. The program utilizes state-of-the-art high-throughput screening of compounds in assays for a wide variety of central nervous system targets. This research is supported by a contract.

Rationale and Objectives:

The global burden and unmet medical need of serious mental illnesses is high. Yet, many large pharmaceutical companies are reducing efforts or exiting drug discovery and development for psychiatric indications. As more of the effort involved in target validation and early stage drug development moves toward the academic sector, support is needed for high-quality data on the activity and selectivity of chemical probes and therapeutic leads. To that end, the PDSP provides a key resource for CNS drug discovery and development efforts, supporting target identification and validation, screening, and lead optimization. As well, PDSP data have been used to support a broad array of basic neuroscience, including structural biology studies, empirical confirmation of computational biology predications, imaging ligand development, and the development of new tools and techniques (e.g., Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)).

PDSP activities include:

1. Screening currently used pharmacologic tools and therapeutics to profile their activity;
2. Screening compounds with physiological or behavioral effects to identify their targets;
3. Selectivity screening of potential new research tools and imaging ligands;
4. In vitro efficacy and counter-screening of potential therapeutics; and
5. Screens of synthetic and natural product libraries.

The program currently conducts screening of more than 400 molecular targets (e.g., G protein coupled receptors, transporters, ion channels), and is one of the largest collections of cloned human and rodent molecular targets available. The PDSP also conducts innovative assay development to incorporate new targets of interest. In addition, the program supports a large database of affinity constants for thousands of compounds at hundreds of targets. These data can be mined to provide starting points for new tool and drug discovery projects or to identify potential new targets for intervention.

Each year, PDSP receives over 100 requests from, most of whom receive NIMH or NIH funding. As well, PSDP tests an average of 4,000 compounds in over 215,000 assays annually. Screening is free of charge to approved investigators from academic and non-profit institutions, as well as NIMH-funded small businesses. The consistently large demand for the program increases each year, and requests have now exceeded capacity. The PDSP is now the standard in the field for academic researchers seeking to develop new tools and therapeutics, with a strong reputation for rigor and data quality.