PT  - JOURNAL ARTICLE
AU  - Alvin V. Terry, Jr
AU  - Jerry J. Buccafusco
AU  - Elizabeth J. Herman
AU  - Patrick M. Callahan
AU  - Wayne D. Beck
AU  - Samantha Warner
AU  - Leah Vandenhuerk
AU  - Kristy Bouchard
AU  - Gary M. Schwarz
AU  - Jie Gao
AU  - James M. Chapman
TI  - The Prototypical Ranitidine Analog JWS-USC-75-IX Improves Information Processing and Cognitive Function in Animal Models
AID  - 10.1124/jpet.110.175422
DP  - 2011 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 751--766
VI  - 336
IP  - 3
4099  - http://jpet.aspetjournals.org/content/336/3/751.short
4100  - http://jpet.aspetjournals.org/content/336/3/751.full
SO  - J Pharmacol Exp Ther2011 Mar 01; 336
AB  - This study was designed to evaluate further a prototypical ranitidine analog, JWS-USC-75-IX, [(3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine, JWS], for neuropharmacologic properties that would theoretically be useful for treating cognitive and noncognitive behavioral symptoms of neuropsychiatric disorders. JWS was previously found to inhibit acetylcholinesterase (AChE) activity, serve as a potent ligand at muscarinic M2 acetylcholine receptors, and elicit positive effects on spatial learning, passive avoidance, and working memory in rodents. In the current study, JWS was evaluated for binding activity at more than 60 neurotransmitter receptors, transporters, and ion channels, as well as for inhibitory activity at AChE and butyrylcholinesterase (BChE). The results indicate that JWS inhibits AChE and BChE at low (micromolar) concentrations and that it is a functional antagonist at M2 receptors (KB = 320 nM). JWS was subsequently evaluated orally across additional behavioral assays in rodents (dose range, 0.03–10.0 mg/kg) as well as nonhuman primates (dose range, 0.05–2.0 mg/kg). In rats, JWS improved prepulse inhibition (PPI) of the acoustic startle response in nonimpaired rats and attenuated PPI deficits in three pharmacologic impairment models. JWS also attenuated scopolamine and (−)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801)-related impairments in a spontaneous novel object recognition task and a five-choice serial reaction time task, respectively. In monkeys, JWS elicited dose-dependent improvements of a delayed match-to-sample task as well as an attention-related version of the task where randomly presented (task-relevant) distractors were presented. Thus, JWS (potentially via effects at several drug targets) improves information processing, attention, and memory in animal models and could potentially treat the cognitive and behavioral symptoms of some neuropsychiatric illnesses.