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 M 2 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 M 2 receptors (K B ϭ 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 (Ϫ)-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.

Synthesis and biological evaluation of ranitidine analogs as multiple-target-directed cognitive enhancers for the treatment of Alzheimer’s disease

“…The activities of these 4-nitropyridazine analogs of JWS are summarized in Table 1. Compounds were evaluated in AChE, 25,28 BuChe 25,28 and M1–M4 assays 29,30 (For Tables 1–3 and 1 µM compound was tested) as previously described. JWS analogs 5–7 possess small aliphatic groups at R1 and R2 and these were found to decrease activity.…”

CNTRICS final animal model task selection: Control of attention

“…The baseline or comparison condition varied across studies, including normal performance by healthy animals, poorly-performing animals, or following degradation of performance by task parameter manipulation or brain lesion, pharmacological treatment or sleep deprivation, Drugs producing performance enhancement, though often under specific conditions, have included the following: D1 dopamine receptor agonists (Granon et al 2000; Chudasama and Robbins 2004, but see also Passetii et al 2003), donepezil (Balducci et al 2003; Lindner et al, 2006; Romberg et al 2011), M2 muscarinic, agonist (Terry et al 2010), alpha-7 and alpha-4, beta4 subunit selective nicotinic receptor agonists (Grottick et al 2003; Mohler et a 2010; Semenova et al 2007), ciproxifan (Ligneau et al 1998), sertindole (Carli et al 2011b), aripiprazole (Carli et al 2010b), clozapine (Amitai and Markou 2007), methylphenidate (Paine et al 2010), adrenergic agents (Jakala et al 1992; Puumala et al 1997) reboxetine (Liu et al 2009) and atomoxetine (Robinson 2012). The 5CSRTT has also been used to study performance in genetically modified mice including a genetic model of attention deficit disorder (Davies et al, 2009) or other impulse-control dysfunction (Isles et al, 2004; Lambourne et al, 2007; Oliver et al, 2009; Yan et al, 2011); a triple-transgenic 3×Tg-AD mouse model of Alzheimer’s Disease (Romberg et al, 2011) and alpha 7 nAChR mutant mice (Hoyle et al, 2006; Young et al, 2004).…”

The prominent role of stimulus processing

“…In rodents and in nonhuman primates, lesions of the cholinergic nucleus basalis of Meynert (nBM) [3] result in impaired performance on learning and memory tasks. Blockade of the cholinergic muscarinic receptors by the antagonist scopolamine results in impaired performance on learning and memory tasks [4,5,6 •• ,7 • ,8] and on tasks of attention [1,9], whereas enhancing cholinergic function improves memory and attention [10]. In healthy humans, scopolamine produces a transitory impairment of a wide range of memory and attention functions [11–14].…”