title: Polyamine modulation of NMDARs as a mechanism to reduce effects of alcohol dependence.
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.
authors.affiliation: Psychology Department, University of Kentucky, Lexington, KY 40506-0044, USA. sbarron@uky.edu
authors.forename: Susan
authors.initials: S
authors.lastname: Barron
authors.forename: Ben
authors.initials: B
authors.lastname: Lewis
authors.forename: Kristen
authors.initials: K
authors.lastname: Wellmann
authors.forename: Megan
authors.initials: M
authors.lastname: Carter
authors.forename: Justin
authors.initials: J
authors.lastname: Farook
authors.forename: Josh
authors.initials: J
authors.lastname: Ring
authors.forename: Dennis Trent
authors.initials: DT
authors.lastname: Rogers
authors.forename: Robert
authors.initials: R
authors.lastname: Holley
authors.forename: Peter
authors.initials: P
authors.lastname: Crooks
authors.forename: John
authors.initials: J
authors.lastname: Littleton
mesh_terms: D000437:Alcoholism / Q000188:drug therapy*; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000523:psychology; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000188:drug therapy; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D018696:Neuroprotective Agents / Q000494:pharmacology; D010330:Patents as Topic; D011073:Polyamines / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors*
chemical_list: D006146:Guanidines; D018696:Neuroprotective Agents; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate