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

Recent Patents on CNS Drug Discovery
Susan BarronJohn M Littleton

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...Continue Reading

Citations

Mar 31, 2012·Addiction Biology·Raye Z LittenAntonio Noronha
May 18, 2016·Alcoholism, Clinical and Experimental Research·Raye Z LittenJoanne B Fertig
Jun 30, 2016·Journal of Medicinal Chemistry·Geoffrey A HeinzlFengtian Xue
Feb 11, 2020·Current Pharmaceutical Design·Vasiliki PardaliGrigoris Zoidis
Jul 28, 2017·The Biochemical Journal·Gregor Laube, Hans-Gert Bernstein

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