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