Recent Patents on CNS Drug Discovery

Vincenzo Di Marzo
Istituto di Chimica Biomolecolare (I.C.B.)
Consiglio Nazionale delle Ricerche (C.N.R.)
Via Campi Flegrei 34
Pozzuoli, Napoli 80078
Italy

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

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.

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Article Details

VOLUME: 7
ISSUE: 2
Page: [129 - 144]
Pages: 16
DOI: 10.2174/157488912800673128