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Novel Dopamine Receptor Ligands as Therapeutics for Central Nervous System Disorders

Posted Jun 13 2010 5:00pm

Description of Invention:
The dopamine D3 receptor subtype is a member of the dopamine D2 subclass of receptors. These receptors have been implicated in a number of CNS disorders, including psychostimulant abuse, psychosis and Parkinson's disease. Compounds that bind with high affinity and selectivity to D3 receptors can not only provide important tools with which to study the structure and function of this receptor subtype, but may also have therapeutic potential in the treatment of numerous psychiatric and neurologic disorders.

The 4-phenylpiperazine derivatives are an important class of dopamine D3 selective ligands. However, due to their highly lipophilic nature, these compounds suffer from solubility problems in aqueous media and reduced bioavailability. To address this problem, a process was designed to introduce functionality into the carbon chain linker of these compounds. Compared to currently available dopamine D3 receptor ligands, the resulting compounds show improved pharmacological properties and D3 selectivities but due to their more hydrophilic nature, these derivatives are predicted to have improved water solubility and bioavailability.

  • Therapeutics for a variety of psychiatric and neurologic disorders
  • Research tools to study D3 receptor structure and function

  • Improved pharmacological properties and selectivity over existing dopamine D3 receptor ligands.
  • Hydrophilic nature likely to lead to improved water solubility and bioavailability

Development Status:
Pre-clinical discovery

Further Development Required:
  • Evaluate selected compounds in animal models of drug abuse, psychosis, obesity and Parkinson's disease
  • Design and synthesize novel, functionalized analogs using both classical and computational drug design to improve D3 receptor affinity and selectivity
  • Evaluate compounds for binding in D3 and D2 receptor expressing cell lines and in in vitro functional assays
  • Correlate in vitro binding affinities with in vivo function in rats and monkeys and evaluate compounds in knockout mice models
  • Pursue PET and SPECT imaging agents by radiolabel of D3 ligands and evaluation in rats and non-human primates

Amy H Newman (NIDA)
Peter Grundt (NIDA)
Jianjing Cao (NIDA)

Patent Status:
HHS, Reference No. E-128-2006/0
US, Application No. 12/664,668 filed 15 Dec 2009

Licensing Status:
Available for licensing

Collaborative Research Opportunity:
The National Institute on Drug Abuse's Medications Discovery Research Branch is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize 4-phenylpiperazine derivatives as dopamine D3 selective ligands. Please contact VioConley, M.S. at 301-435-2031 or for more information.

Central Nervous System
Central Nervous System - Therapeutics
In-vitro Data

For Additional Information Please Contact:
Charlene Sydnor Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-4689
Fax: 301-402-0220

Ref No: 1985

Updated: 06/2010

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