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.

Fig. 1.

A, effects of JWS on locomotor activity and motor function. A, effects of oral administration of JWS (compared with the second-generation antipsychotic risperidone) on amphetamine (1.0 mg/kg s.c.)-induced locomotor activity (total photobeam breaks). B, effects of oral administration of the first-generation antipsychotic haloperidol (HAL), JWS alone, and JWS combined with haloperidol on the mean catalepsy score. C, effects of oral administration of JWS (compared with haloperidol) in the rotarod task. D, effects of oral administration of haloperidol compared with JWS (n = 11–14) on conditioned avoidance responding. Decreases in avoidance responses and increases in response failures produced by haloperidol and the lack of effects of JWS in rats where behavior was maintained under a discrete-trial avoidance schedule are illustrated. VEH, vehicle.

Fig. 2.

A, effects of oral administration of JWS on the percentage of PPI in rats for three prepulse intensities (5, 10, and 15 db above background). B, JWS effects on the mean startle amplitude to a 120-db, 20-ms noise burst. C, JWS effects on the percentage of prepulse inhibition averaged across the three prepulse intensities. Bars represent mean ± S.E.M. for each treatment. VEH, vehicle. *, p < 0.05, significantly different from vehicle controls; †, p < 0.09. n = 12 to 18 rats per group.

Fig. 3.

A, effects of apomorphine (0.5 mg/kg s.c.) and several oral doses of JWS on apomorphine-induced deficits in prepulse inhibition in rats associated with three prepulse intensities (75, 80, and 85 db). A reference dose of risperidone (0.3 mg/kg) was included as a positive control for attenuating the effects of apomorphine. B, effects of apomorphine and JWS combined with apomorphine on startle amplitude. C, effects of 0.5 mg/kg apomorphine and several doses of JWS on apomorphine-induced deficits in prepulse inhibition averaged across prepulse levels. Bars represent mean ± S.E.M. for each treatment (n = 8–10). VEH, vehicle; APO, apomorphine; RISP, risperidone. #, p < 0.05, significantly different from the vehicle-associated response. *, p < 0.05, significantly different from the apomorphine-associated response. †, nearly significantly (p < 0.09) different from the apomorphine-associated response.

Fig. 4.

A, effects of MK-801 (0.1 mg/kg s.c.) and several oral doses of JWS on MK-801-induced deficits in prepulse inhibition in rats associated with three prepulse intensities (75, 80, and 85 db). A reference dose of risperidone (0.3 mg/kg) was included as a positive control for attenuating the effects of MK-801. B, effects of MK-801 and JWS combined with MK-801 on startle amplitude. C, effects of JWS on MK-801-induced deficits in prepulse inhibition averaged across prepulse levels. Bars represent mean ± S.E.M. for each treatment (n = 10). VEH, vehicle; MK, MK-801; RISP, risperidone. #, p < 0.05, significantly different from the vehicle-associated response. *, p < 0.05, significantly different from the MK-801-associated response; †, p < 0.08, nearly significantly different from the MK-801-associated response.

Fig. 5.

A, effects of scopolamine (0.33 mg/kg i.p.) and several oral doses of JWS on scopolamine-induced deficits in prepulse inhibition in rats associated with three prepulse intensities (75, 80, and 85 db). A reference (oral) dose of donepezil (2.0 mg/kg) was included as a positive control for attenuating the effects of scopolamine. B, effects of scopolamine and JWS combined with scopolamine on startle amplitude. C, effects of JWS on scopolamine-induced deficits in prepulse inhibition averaged across prepulse levels. Bars represent mean ± S.E.M. for each treatment (n = 8–10). VEH, vehicle; SCOP, scopolamine; DON, donepezil. #, p < 0.05, significantly different from the vehicle associated response. *, p < 0.05, significantly different from the scopolamine-associated response; †, p < 0.08, nearly significantly different from the scopolamine-associated response.

Fig. 6.

Effects of scopolamine (0.33 mg/kg i.p.) and several oral doses of JWS on scopolamine-induced deficits in the performance of a spontaneous novel object recognition task. A reference (oral) dose of donepezil (2.0 mg/kg) was included as a positive control for attenuating the effects of scopolamine. The illustrations at the left indicate the preference for the novel object compared with the familiar object (*, p < 0.05) at each of the three delays. The inset at right illustrates drug effects (averaged across delays) on the “discrimination index” (d2), which refers to the proportion of the total exploration time the animal spent investigating the novel object (see Materials and Methods). VEH, vehicle; SCOP, scopolamine; DON, donepezil. +, p < 0.01, significantly different from vehicle control performance. Data are expressed as the mean ± S.E.M. n = 12 to 18 rats per group.

Fig. 7.

A, effects of JWS on the performance of a variable stimulus duration version of the 5C-SRTT. Rats (n = 6) were trained to meet specific performance criterion (described under Materials and Methods) at SD of 0.5 s. Then, shorter SDs (0.10 and 0.25 s) were presented pseudorandomly along with the 0.5-s SD. Vehicle (V) and three doses of JWS (administered orally 30 min before testing) were evaluated for effects on task accuracy (percentage correct), the percentage of premature (Prem) responses, and the percentage of perseverative (Perserv) responses. B, effects of JWS on MK-801-related impairments in the standard version of 5C-SRTT with a 0.5-s stimulus duration (n = 12). Vehicle and several doses of JWS (administered orally 30 min before testing) were evaluated for their ability to attenuate the negative effects of MK-801 (administered subcutaneously 10 min before testing). Each bar represents the mean ± S.E.M. for each test group. *, p < 0.05, significantly different compared with vehicle-associated performance level. +, p < 0.05, significantly different compared with MK-801-associated performance level (ANOVA).

Fig. 8.

Effects of JWS on DMTS performance in monkeys. The dose-effect relationship for each delay in the DMTS task in nine adult pigtail macaques 30 min after the oral administration of JWS is shown. Each bar represents the mean (percentage correct) ± S.E.M. over 96 trials per session. The baseline (vehicle) was determined from the average of all vehicle sessions run throughout the study. *, p < 0.05 compared with vehicle baseline levels of DMTS accuracy.

Fig. 9.

The effect of JWS on the performance in the distractor version of the DMTS-D in monkeys. The dose-effect relationship for each delay in the DMTS-D task in nine adult pigtail macaques 30 min after the oral administration of JWS is illustrated. Top, nondistractor-related accuracies (72 trials) are plotted as a function of dose for each of four task delay intervals. Bottom, distractor-related accuracies (24 trials) are plotted as a function of dose for each of three task delay intervals. Mean accuracies associated with the standard DMTS task are included for comparison. Bottom inset, distractor-related accuracies averaged across delays. Each bar represents the mean ± S.E.M. VEH, vehicle. *, p < 0.05, significantly different compared with respective vehicle DMTS (nondistractor) mean; +, p < 0.05, significantly different compared with vehicle DMTS-D (distractor) mean. †, p < 0.09 compared with vehicle DMTS-D mean.