Polyamine modulation of NMDARs as a mechanism to reduce effects of alcohol dependence

Susan Barron, Ben Lewis, Kristen Wellmann, Megan Carter, Justin Farook, Josh Ring, Dennis Trent Rogers, Robert Holley, Peter Crooks, John Littleton

Research output: Contribution to journalReview articlepeer-review

18 Scopus citations

Abstract

Relapse and neurodegeneration are two of the major therapeutic targets in alcoholism. Fortuitously, the roles of glutamate/NMDA receptors (NMDARs) in withdrawal, conditioning and neurotoxicity mean that NMDAR inhibitors are potentially valuable for both targets. Preclinical studies further suggest that inhibitory modulators that specifically reduce the co-agonist effects of polyamines on NMDARs are potential non-toxic medications. Using agmatine as a lead compound, over 1000 novel compounds based loosely on this structure were synthesized using feedback from a molecular screen. A novel series of aryliminoguanidines with appropriate NMDAR activity in the molecular screen were discovered (US patent application filed 2007). The most potent and selective aryliminoguanidine, JR 220 [4- (chlorobenzylidenamino)- guanidine hydrochloride], has now been tested in a screening hierarchy for anti-relapse and neuroprotective activity, ranging from cell-based assay, through tissue culture to animal behavior. This hierarchy has been validated using drugs with known, or potential, clinical value at these targets (acamprosate (N-acetyl homotaurine), memantine and topiramate). JR220 was non-toxic and showed excellent activity in every screen with a potency 5-200x that of the FDA-approved anti-relapse agent, acamprosate. This chapter will present a review of the background and rationale for this approach and some of the findings garnered from this approach as well as patents targeting the glutamatergic system especially the NMDAR.

Original languageEnglish
Pages (from-to)129-144
Number of pages16
JournalRecent Patents on CNS Drug Discovery
Volume7
Issue number2
DOIs
StatePublished - Aug 2012

Keywords

  • NR2B neuroprotection
  • Polyamine
  • Relapse

ASJC Scopus subject areas

  • Drug Discovery
  • Psychiatry and Mental health
  • Pharmacology (medical)

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