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 (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.
Footnotes
This work was supported by the National Institutes of Health National Institute on Aging [Grant AG032140] and the Institute for the Study of Aging [Grant 271225]. Salary support was also provided through a Merit Review Award from the Veterans Administration (to J.J.B.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.175422.
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ABBREVIATIONS:
- AChEI
- acetylcholinesterase inhibitors
- NMDA
- N-methyl-d-aspartate
- AD
- Alzheimer's disease
- AChE
- acetylcholinersterase
- JWS
- JWS-USC-75-IX, 3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine
- MK-801
- (−)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate
- DMSO
- dimethylsulfoxide
- CAR
- conditioned avoidance responding
- PPI
- prepulse inhibition
- NOR
- novel object recognition
- OR
- object recognition
- d2
- discrimination index
- 5C-SRTT
- five-choice serial reaction time task
- DMTS
- delayed match-to-sample
- DMTS-D
- delayed match-to-sample with distractor
- ANOVA
- analysis of variance
- BChE
- butyrylcholinesterase.
- Received September 22, 2010.
- Accepted November 12, 2010.
- U.S. Government work not protected by U.S. copyright
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