Pharmacological characterization of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2, 3-dihydro-1H-inden-2-yl]-2-propanesulfonamide: a novel, clinical AMPA receptor positive allosteric modulator

Abstract

Background and purpose: AMPA receptor positive allosteric modulators represent a potential therapeutic strategy to improve cognition in people with schizophrenia. These studies collectively constitute the preclinical pharmacology data package used to build confidence in the pharmacology of this molecule and enable a clinical trial application.

Experimental approach: [N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro 1H-inden-2-yl]-2-propanesulfonamide] (UoS12258) was profiled in a number of in vitro and in vivo studies to highlight its suitability as a novel therapeutic agent.

Key results: We demonstrated that UoS12258 is a selective, positive allosteric modulator of the AMPA receptor. At rat native hetero-oligomeric AMPA receptors, UoS12258 displayed a minimum effective concentration of approximately 10 nM in vitro and enhanced AMPA receptor-mediated synaptic transmission at an estimated free brain concentration of approximately 15 nM in vivo. UoS12258 reversed a delay-induced deficit in novel object recognition in rats after both acute and sub-chronic dosing. Sub-chronic dosing reduced the minimum effective dose from 0.3 to 0.03 mg·kg^-1 . UoS12258 was also effective at improving performance in two other cognition models, passive avoidance in scopolamine-impaired rats and water maze learning and retention in aged rats. In side-effect profiling studies, UoS12258 did not produce significant changes in the maximal electroshock threshold test at doses below 10 mg·kg^-1 .

Conclusion and implications: We conclude that UoS12258 is a potent and selective AMPA receptor modulator exhibiting cognition enhancing properties in several rat behavioural models superior to other molecules that have previously entered clinical evaluation.

Figure 1

Concentration–response curve and chemical structure for UoS12258 showing its potentiation of glutamate‐induced rises in intracellular calcium in HEK293 cells stably expressing the hGluA2i homomeric AMPA receptor, pEC₅₀ = 5.57. Responses are normalized to 150 μM cyclothiazide. Mean ± SEM, n = 6 independent experiments.

Figure 2

(A) Representative whole cell current traces recorded from a single HEK293 cell expressing hGluA2i homomeric AMPA receptors. UoS12258 (1–100 μM, upper concentration limited by solubility) produced a concentration‐dependent and reversible increase in charge transfer. Positive modulator, cyclothiazide (CTZ) 30 μM, also increased charge transfer following application of glutamate (line 7). (B) Concentration–response curve for the potentiation of hGluA2i‐mediated inward currents by UoS12258, pEC₅₀ = 5.19. Responses are normalised to 30 μM cyclothiazide. n = 4 independent experiments.

Figure 3

Rat native neuronal data. (A) Concentration‐response plot for UoS12258‐mediated potentiation of charge transfer. (B) Concentration‐response plot for UoS12258‐mediated potentiation of AMPA receptor deactivation. (C) Concentration–response plot for the inhibition of AMPA receptor desensitization induced by UoS12258. Responses were normalized to 30 μM AMPA control. Lowest concentration to cause a significant (*P < 0.05) difference.

Figure 4

Representative traces recorded from the dentate gyrus of the anaesthetized rat following vehicle (left trace) and 0.1 mg·kg⁻¹ i.v. administration of UoS12258 (right trace). Synaptic traces are an average of 10 consecutive responses; the population spike is ringed in blue.

Figure 5

(A) Effects of UoS12258 on NOR in rats after acute administration (0.1–1 mg·kg⁻¹ p.o., 4 h prior to T1 and T2); (B) Effects of UoS12258 on NOR in rats after 7 day sub‐chronic administration (0.003–0.03 mg·kg⁻¹ p.o. dosed daily for 7 days and then 4 h prior to T1 and T2). Statistical analysis was performed using ANOVA, followed by planned comparisons (*P < 0.05) to vehicle‐treated animals.

Figure 6

Effects of acute UoS12258 and SB‐399885T on scopolamine‐induced impairment of a passive avoidance response in adult Wistar rats. Data represent mean ± SEM avoidance latency at the 24 h recall time. Significant difference (*P < 0.05) compared to scopolamine‐treated animals (Mann–Whitney U‐test, n = 6 per group).

Figure 7

Effect of sub‐chronic UoS12258 on acquisition of a water maze spatial learning task by aged Wistar rats. Data represent mean ± SEM escape latency (s) averaged over the five trials of each training session. By session 3 there was a significant, P < 0.05, difference between groups administered either 3 or 10 mg·kg⁻¹ compared to vehicle treated animals (n = 6 per group).

Figure 8

Effect of sub‐chronic UoS12258 on recall of a water maze spatial task by aged rats. Data represent mean ± SEM time (s) swimming in the target quadrant of the water maze during probe trials 1, 3 and 7 days post‐training. Significant difference (*P < 0.05) compared to vehicle treated animals.

Figure 9

Changes in levels of ACh and dopamine (DA) expressed as % changes from basal (line graphs) and total efflux (bar chart – calculated as AUC of % changes from basal levels) in the anterior cingulate cortex (left panel) and dorsal hippocampus (right panel) following administration of UoS12258 (0.1, 0.3 and 1.0 mg·kg⁻¹, p.o). *P < 0.05, significant differences compared to vehicle treated animals.