title: The prototypical ranitidine analog JWS-USC-75-IX improves information processing and cognitive function in animal models.
abstract: 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 (K(B) = 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.
authors.affiliation: Department of Pharmacology and Toxicolog, Medical College of Georgia, Augusta, Georgia, USA. aterry@mcg.edu
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Buccafusco
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Herman
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Callahan
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Beck
authors.forename: Samantha
authors.initials: S
authors.lastname: Warner
authors.forename: Leah
authors.initials: L
authors.lastname: Vandenhuerk
authors.forename: Kristy
authors.initials: K
authors.lastname: Bouchard
authors.forename: Gary M
authors.initials: GM
authors.lastname: Schwarz
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: James M
authors.initials: JM
authors.lastname: Chapman
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D005260:Female; D008254:Macaca nemestrina; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011899:Ranitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology
chemical_list: D011899:Ranitidine