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#4 - Novel Dopamine D2 Receptor Antagonists and Methods of Their Use
Long Title: Novel Dopamine D2 Receptor Antagonists and Methods of Their Use
NIH Reference No.: E-030-2013
Executive Summary
General Description
G-protein-coupled receptors (GPCRs) are among the most intensely investigated drug targets in the pharmaceutical industry. Dopamine receptors (DARs) belong to the large superfamily of neurotransmitter and hormone GPCRs. There are five subtypes of DARs identified in the mammalian genome, D1-D5. Among the DARs, the D2 DAR is arguably one of the most validated drug targets in neurology and psychiatry. For example, the D2 DAR is therapeutically targeted in Parkinson’s Disease, restless legs syndrome, Tourette’s syndrome, hyperprolactinemia, Huntington’s chorea, and schizophrenia. However, most of the current drugs targeting the D2 DAR are problematic due to off-target cross-GPCR reactivity. Among the various subtypes of DARs, D2 and D3 DARs share 78% homology making it a challenge to identify small molecules that specifically bind to D2 DAR. Thus, there is an unmet medical need for a drug that specifically binds to the D2 DAR for treating neuropsychiatric and endocrine disorders.
Scientific Progress
In a collaborative study with NCATS, a series of novel selective small molecule antagonists of the D2 DAR were identified from a high-throughput screening campaign. Among the compounds identified, the lead compound has a structure different from all other (non-selective) D2 antagonist-like compounds. The inventors found that the lead compound has higher selectivity for D2 compared to the other DAR subtypes and does not show significant cross-reactivity to other GPCRS, such as those for serotonin, muscarinic acetylcholine, and histamine receptors. In addition, results from in vivo rodent studies show that the lead compound affects D2- but not D3-mediated behaviors, further demonstrating high specificity to the D2 pathway. Finally, in vivo PET imaging in a non-human primate model shows that, when administered, the lead compound occupies the D2 DAR in the brain thus demonstrating that it readily crosses the blood-brain barrier and binds to the D2 DAR in vivo.
Future Direction
Strengths
Weaknesses
Patent Status
U.S. Application No. 61/859532 filed 29 July 2013
Relevant Publications
Xiao, J., et al., J. Med. Chem., 2014 Apr 24; 57 (8), pp 3450–3463 (PMID: 24666157)
Inventor Bio
David Sibley, Ph.D.
Dr. Sibley received his B.S. degree in Biology from San Diego State University and his Ph.D. in Physiology/Pharmacology from the University of California, San Diego where he worked with Ian Creese studying the ligand binding properties of dopamine receptors. He subsequently carried out postdoctoral work with Robert Lefkowitz at Duke University where he characterized adrenergic receptor regulatory mechanisms. Dr. Sibley moved to the NINDS in 1987 and was appointed Chief of the Molecular Neuropharmacology Section in 1992. His laboratory is currently investigating the molecular, cellular and biochemical properties of dopamine receptors and their role in neuronal signaling.
NIH Reference No.: E-030-2013
Executive Summary
- Intention Type: Therapeutic
- Patent Status: US application filed in 2013, pending approval
- LINK: http://www.ott.nih.gov/technology/e-030-20130
- NIH Reference Number: E-030-2013
- NIH Institute or Center: National Institute of Neurological Disorders and Stroke (NINDS)
- Disease focus: Neuropsychiatric and endocrine disorders, such as, schizophrenia, psychosis, bipolar disorder, Tourette’s syndrome, Huntington’s chorea, depression or hyperprolactinemia
- Basis of Invention: Small molecule
- How it works: The optimized molecule may be a useful as an in vivo probe for studying signal modulation by the D2 dopamine receptor (DAR) subtype. It could also serve as a lead compound for the development of D2 DAR-selective drugs for the treatment of multiple neuropsychiatric and endocrine disorders
- Lead Inventors: David Sibley (NINDS)
- Development Stage: Pre-clinical, proof-of-concept in vitro data available, in vivo animal data available
- Novelty: Highly selective
- Clinical Application: Could be used as an antipsychotic agent, a treatment for schizophrenia, bipolar disorder, Tourette's syndrome, and/or depression. This could also serve as an alternative therapy for disorders currently treated with non-selective D2 antagonists
General Description
G-protein-coupled receptors (GPCRs) are among the most intensely investigated drug targets in the pharmaceutical industry. Dopamine receptors (DARs) belong to the large superfamily of neurotransmitter and hormone GPCRs. There are five subtypes of DARs identified in the mammalian genome, D1-D5. Among the DARs, the D2 DAR is arguably one of the most validated drug targets in neurology and psychiatry. For example, the D2 DAR is therapeutically targeted in Parkinson’s Disease, restless legs syndrome, Tourette’s syndrome, hyperprolactinemia, Huntington’s chorea, and schizophrenia. However, most of the current drugs targeting the D2 DAR are problematic due to off-target cross-GPCR reactivity. Among the various subtypes of DARs, D2 and D3 DARs share 78% homology making it a challenge to identify small molecules that specifically bind to D2 DAR. Thus, there is an unmet medical need for a drug that specifically binds to the D2 DAR for treating neuropsychiatric and endocrine disorders.
Scientific Progress
In a collaborative study with NCATS, a series of novel selective small molecule antagonists of the D2 DAR were identified from a high-throughput screening campaign. Among the compounds identified, the lead compound has a structure different from all other (non-selective) D2 antagonist-like compounds. The inventors found that the lead compound has higher selectivity for D2 compared to the other DAR subtypes and does not show significant cross-reactivity to other GPCRS, such as those for serotonin, muscarinic acetylcholine, and histamine receptors. In addition, results from in vivo rodent studies show that the lead compound affects D2- but not D3-mediated behaviors, further demonstrating high specificity to the D2 pathway. Finally, in vivo PET imaging in a non-human primate model shows that, when administered, the lead compound occupies the D2 DAR in the brain thus demonstrating that it readily crosses the blood-brain barrier and binds to the D2 DAR in vivo.
Future Direction
- Test the therapeutic effects of the lead compound in animal models (e.g., rat and monkey) of neuropsychiatric (schizophrenia) and endocrine disorders.
- Clinical trials for IND planned
Strengths
- Highly selective D2 DAR antagonist
- Potentially fewer side-effects given no apparent off-target cross-reactivity to other neuronal GPCRs
- Able to cross the blood-brain-barrier
Weaknesses
- Early stage invention, in vivo toxicity assay is required for future R&D
Patent Status
U.S. Application No. 61/859532 filed 29 July 2013
Relevant Publications
Xiao, J., et al., J. Med. Chem., 2014 Apr 24; 57 (8), pp 3450–3463 (PMID: 24666157)
Inventor Bio
David Sibley, Ph.D.
Dr. Sibley received his B.S. degree in Biology from San Diego State University and his Ph.D. in Physiology/Pharmacology from the University of California, San Diego where he worked with Ian Creese studying the ligand binding properties of dopamine receptors. He subsequently carried out postdoctoral work with Robert Lefkowitz at Duke University where he characterized adrenergic receptor regulatory mechanisms. Dr. Sibley moved to the NINDS in 1987 and was appointed Chief of the Molecular Neuropharmacology Section in 1992. His laboratory is currently investigating the molecular, cellular and biochemical properties of dopamine receptors and their role in neuronal signaling.
