Skip to main content

Polyamine Modulation of NMDARs as a Mechanism to Reduce Effects of Alcohol Dependence

Buy Article:

$113.00 plus tax (Refund Policy)


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.

Keywords: NR2B neuroprotection; polyamine; relapse

Document Type: Research Article


Affiliations: Psychology Department, University of Kentucky, Lexington, KY 40506-0044.

Publication date: August 1, 2012

More about this publication?
  • Recent Patents on CNS Drug Discovery publishes review articles on recent patents in the field of CNS drug discovery e.g. novel bioactive compounds, analogs & targets. A selection of important and recent patents on CNS drug discovery is also included in the journal. The journal is essential reading for all researchers involved in CNS drug design and discovery.

Access Key

Free Content
Free content
New Content
New content
Open Access Content
Open access content
Subscribed Content
Subscribed content
Free Trial Content
Free trial content
Cookie Policy
Cookie Policy
Ingenta Connect website makes use of cookies so as to keep track of data that you have filled in. I am Happy with this Find out more