This study was designed to further evaluate a prototypical ranitidine analog, JWS-USC-75-IX, (JWS), for neuropharmacologic properties that would theoretically be useful for treating cognitive and non-cognitive behavioral symptoms of neuropsychiatric disorders. JWS was previously found to inhibit acetylcholinesterase (AChE) activity, to serve as a potent ligand at muscarinic (M2) acetylcholine receptors, and to 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, and for inhibitory activity at AChE and butyrylcholinseterase (BChE). The results indicated that JWS inhibits AChE and BChE at low (μM) 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 to 10.0 mg/kg) as well as non-human primates (dose range 0.05 to 2.0 mg/kg). In rats, JWS improved prepulse inhibition (PPI) of the acoustic startle response in non-impaired rats and it attenuated PPI deficits in three pharmacologic impairment models. JWS also attenuated scopolamine and 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 (DMTS) 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 may have potential to treat the cognitive and behavioral symptoms of some neuropsychiatric illnesses.
- Received September 22, 2010.
- Revision received November 12, 2010.
- Accepted November 12, 2010.
- The American Society for Pharmacology and Experimental Therapeutics