Title:Polyamine Modulation of NMDARs as a Mechanism to Reduce Effects of Alcohol Dependence
VOLUME: 7 ISSUE: 2
Author(s):Susan Barron, Ben Lewis, Kristen Wellmann, Megan Carter, Justin Farook, Josh Ring, Dennis Trent Rogers, Robert Holley, Peter Crooks and John Littleton
Affiliation:Psychology Department, University of Kentucky, Lexington, KY 40506-0044.
Keywords:NR2B neuroprotection, polyamine, relapse
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.
