The NIMH complements support of investigator-initiated grants in the area of treatment research through specific initiatives developed to stimulate and facilitate drug discovery and development initiatives. These initiatives are intended to encourage investigators interested in developing new therapeutics or novel ways to test candidate compounds, including new assays or model systems to evaluate potential efficacy and utility in the treatment of mental disorders. The initiatives span the breadth of the drug development process, from target identification and ligand discovery, to preclinical development.
The NIMH has identified several opportunities for linking molecular neuroscience with efforts to facilitate both drug and tool discovery relevant to mental disorders. In order to address the needs of a diverse set of researchers interested in advancing the study of novel compounds towards these goals, the NIMH established contract services for drug screening, synthesis, and preclinical toxicology studies.
The NIMH Psychoactive Drug Screening Program
is a resource program that provides screening of novel psychoactive compounds for pharmacological and functional activity at cloned human or rodent CNS receptors, channels, and transporters (http://pdsp.med.unc.edu/
). The contract also provides assays for predicting bioavailability and cardiovascular toxicity and supports a Ki database of affinity constants for ligand binding (http://pdsp.med.unc.edu/pdsp.php
The NIMH Chemical Synthesis and Drug Supply Program
synthesizes and distributes novel research chemicals, psychoactive drugs, positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging ligand precursors, and compounds that are unavailable to the scientific community from commercial sources to stimulate basic and clinical research relevant to mental health (http://nimh-repository.rti.org/
). The repository contains more than 350 compounds, which are available for research use, and has just begun to distribute screening plates of the inventory in 96-well format. In addition, the program has the capability to provide limited Good Manufacturing Practice (GMP) synthesis of promising candidate compounds for use in clinical studies.
The NIMH Toxicological Evaluation of Novel Ligands Program
advances the discovery of neuroimaging biomarkers by providing toxicology and safety assessment services for promising, target-selective ligands for PET, SPECT, or magnetic resonance imaging studies (MRI) in humans (http://www.sri.com/biosciences/nimh/nimh-tox.html
). The program also provides limited assessment of novel psychoactive agents for clinical research and as potential therapeutics. Toxicology and safety data generated by the program are used to support exploratory Investigational New Drug (IND) applications to the FDA for human studies. The program has conducted toxicological evaluation of more than a dozen novel imaging ligands for G-protein coupled receptors (GPCRs), transporters, and metabotropic glutamate receptor subtypes as well as pharmacokinetic and bioavailability assessment of three novel clinical candidates.
The NIH Roadmap Molecular Libraries Program
has established a translational high-throughput screening (HTS) screening resource in the academic environment to improve the understanding of biology and disease mechanisms (http://nihroadmap.nih.gov/molecularlibraries/
). At the core of this initiative is the Molecular Libraries Screening Centers Network
; the Molecular Libraries Probe Production Centers or MLPCN beginning in July 2008 as the program moves into the production phase). The MLSCN optimizes and performs HTS to identify to identify compounds that are active in biochemical, cell-based or model organism assays using multiple screening formats including target-based, reporter and phenotypic screens. Active compounds identified through initial screening of the library (v.i., the Small Molecule Repository) are optimized through a combination of structure-activity analysis and synthetic chemistry to obtain useful chemical probes that can be used to study the functions of genes, cells, and biochemical pathways. NIH anticipates that these projects will also facilitate the development of new drugs by providing early stage chemical compounds that will enable researchers in the public and private sectors to validate new drug targets, which could then move into the drug development pipeline. For example, the availability of small molecule probes to characterize the biology of genes of interest, cellular processes, and proteins associated with disease processes will further advance our knowledge of nervous system pathophysiology and unveil additional targets for new therapeutic approaches to human diseases, including psychosis, depression, anxiety, pain and aging-associated neurodegenerative disorders.
In its pilot phase, the MLSCN consortium included one intramural and nine extramural centers with expertise in assay development, HTS, chemistry and informatics. Compounds screened by the network of centers are maintained within the Small Molecule Repository
that was established in 2004 and currently has a set of approximately 300,000 compounds of specified purity, quantity, and solubility (http://mlsmr.glpg.com/MLSMR_HomePage/
). The library contains structures not typically found in commercial collections or those housed in pharmaceutical companies. Sources of these unique structures include: natural products and novel compounds libraries prepared by academic investigators through the Pilot Scale Libraries
); compounds generated by the Centers for Chemical Methodologies and Library Development
); and those obtained through an NIH solicitation (http://grants.nih.gov/grants/guide/notice-files/NOT-RM-07-005.html
). The library of compounds has been assayed in more than 200 biological targets to date.
Data generated by the MLSCN centers including assay descriptions, chemical structures, and biological assay and profiling data for individual compounds are available in PubChem,
a publicly accessible database maintained by the National Library of Medicine (http://pubchem.ncbi.nlm.nih.gov/
). Investigators in the public and private sector have access to resources of the screening centers, on a competitive basis, through HTS
and Assay Development
), by submitting compounds to the Small Molecule Repository for screening, and through PubChem. In addition, the NIH Clinical Collection
, a plated array of 450 drugs that have been in clinical testing, is available to researchers at cost (http://www.nihclinicalcollection.com/
) to enable bench-top screening. These compounds may serve as starting points for medicinal chemistry optimization efforts and, in some cases, may even be appropriate for use in new disease areas (i.e., drug repurposing, see Chong and Sullivan, 2007
). Chemical probes are emerging from the MLSCN at an increasing rate for a variety of targets and cell phenotypes, many in the CNS area (see, Huang et al, 2007
; Lewis et al, 2008
; Niswender et al, 2008
; Skoumbourdis et al, 2008
; Titus et al, 2008
). More information on this Molecular Libraries effort is available (Austin et al, 2004
; Huryn and Cosford, 2008
; Lazo et al, 2007
NIH Rapid Access to Interventional Development (NIH-RAID)
is an NIH Roadmap pilot program intended to reduce some of the common barriers (the ‘valley of death’) in the small molecule development pipeline from preclinical discovery to clinical testing (http://nihroadmap.nih.gov/raid/
). The goal of the NIH-RAID pilot is to make available, on a competitive basis, certain critical resources needed for the development of therapeutic agents. NIH contract services supported by the program include: scale-up production, bulk supply, and GMP manufacturing of small molecule drugs for phase I studies, formulation development, development of bioanalytical assays for pharmacokinetic studies, range-finding and IND-directed toxicology, and product development planning to support IND filing. Academic investigators are invited to submit resource access applications in response to the program announcement (http://grants.nih.gov/grants/guide/pa-files/PAR-07-358.html
). The program does not support in vitro
or in vivo
testing or production of materials for studies beyond phase I. Contract services have assisted in the development of several, novel CNS therapeutic agents through the NIH-RAID program with co-funding from NIMH and the neuroscience institutes. Examples of approved projects include: vasopressin 1A antagonist SRX246 for treating anxiety and depression; M1 muscarinic agonist CDD-0102A for the treatment of Alzheimer's disease; and kappa opioid receptor antagonist JDTic for treating drug abuse (cocaine relapse), depression, and schizophrenia (http://nihroadmap.nih.gov/raid/ApprovedProjects.aspx
To maximize the potential for translating basic molecular science into treatment and tool discoveries, the Drug Discovery for Nervous System Disorders
initiative specifically encourages the submission of applications aimed at drug discovery and early preclinical testing of compounds with therapeutic potential (http://grants.nih.gov/grants/guide/pa-files/PAR-07-048.html
). The initiative encourages studies aimed at design, synthesis, and preclinical testing of compounds, development of novel delivery systems, and cell based assays for screening of candidate compounds for efficacy and/or toxicity. The announcement also encourages the development of novel assays using model organisms or behavioral systems for preliminary screening or further evaluation of candidate compounds, including in vivo
models that emulate critical features of specific CNS disorders. Model development under these funding opportunities should be directed toward assessing potential efficacy rather than elucidating disease mechanisms. Applications submitted in response to this announcement are directed to Neural Drug Discovery
, a Special Emphasis Review Panel convened by the Center for Scientific Review (http://www.csr.nih.gov/Roster_proto/allother_sep.asp
). Projects funded through this initiative by NIMH have examined a range of promising targets for mental disorders including subtype selective benzodiazepine ligands, peptide receptor ligands, metabotropic glutamate receptor potentiators, and GSK-3 beta inhibitors.
The discovery and application of novel imaging ligands holds promise for both facilitating drug discovery and for identifying molecular and cellular pathways implicated in psychiatric disorders as targets for treatment development. NIMH supports the development of imaging ligands through initiatives such as the Development and Application of PET and SPECT Imaging Ligands as Biomarkers for Drug Discovery and for Pathophysiological Studies of CNS Disorde
. This initiative encourages applications aimed at developing novel radioligands for PET or SPECT imaging in human brain to facilitate the broad application of neuroimaging probes in pathophysiological studies, drug discovery/development research, and in biomarker development/qualification studies as quantifiable indicators of disease progression and treatment efficacy (http://grants.nih.gov/grants/guide/pa-files/PA-06-461.html
). Projects supported by NIMH in response to this initiative include the development of radiotracers for targets including GPCRs, transporters, glutamate receptor subtypes, and beta-amyloid. Some of these projects have involved collaborations with private sector partners.