Methods of making and using dopamine receptor selective antagonists/partial agonists


Dopamine is a major neurotransmitter in the central nervous system and among other functions is directly related to the rewarding effects of drugs of abuse.  Dopamine signaling is mediated by D1, D2, D3, D4 and D5 receptors.  The dopamine D3 receptor is a known target to treat a variety of neuropsychiatric disorders, including substance use disorders (e.g. cocaine and opioid), schizophrenia and depression.  Despite extensive efforts, it has proven difficult to identify a lead molecule that selectively binds to D3 receptors (versus D2 receptors, for example), with the desired pharmacological and pharmacokinetic profile.  For example, metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse.

The library of compounds of this technology is designed to have high affinity and specificity for the dopamine D3 receptor.  Preliminary studies at NIDA indicate that selected lead compounds have promising in vivo activity in rodents, including reduced acquisition to self-administration of oxycodone, inhibition of reinstatement to oxycodone seeking, and ameliorating naloxone-precipitated withdrawal from oxycodone dependence, and that these lead compounds are metabolically stable.



Potential Commercial Applications: Competitive Advantages:
  • Treatment of Opioid Use Disorders, Schizophrenia, Bipolar Disorder, and of cannabis (Tetrahydrocannabinol, THC) dependence
 
  • Despite extensive efforts to develop  D3 receptor-selective compounds, it has proven difficult to identify a ligand with the desired pharmacological and pharmacokinetic profile for translation to the clinic.   The D3 receptor ligands described herein may be useful to treat a variety of diseases, including opioid use disorders and schizophrenia.


Development Stage:
Pre-clinical (in vivo)

Inventors:

Amy Newman (NIDA)  ➽ more inventions...

Vivek Kumar (NIDA)  ➽ more inventions...


Intellectual Property:
International Application No. 16/084093
EP Application No. PCT/US2017/02132
Canada Application No. 17711971.6
Application No. 3017342

Publications:
A. Newman et al. PMID: 27508895

Collaboration Opportunity:

Licensing and research collaboration


Licensing Contact:
John Hewes, Ph.D.
Email: John.Hewes@nih.gov
Phone: 240-276-5515

OTT Reference No: E-053-2016
Updated: Nov 13, 2018