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 PURPOSEAMPA 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 RESULTSWe demonstrated that UoS12258 is a selective, positive allosteric modulator of the AMPA receptor. At rat native heterooligomeric 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. Subchronic dosing reduced the minimum effective dose from 0.3 to 0.03 mg·kg À1 . 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 À1 . CONCLUSION AND IMPLICATIONSWe 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. AbbreviationsMEST, maximal electroshock seizure threshold test; NOR, novel object recognition

Pharmacological characterisation of MDI-222, a novel AMPA receptor positive allosteric modulator with an improved safety profile

“…In contrast, UoS12258 produced a marked reduction in the threshold such that at a dose (100 mg/kg p.o.) giving a brain exposure of around 5.0 µg/g, the proconvulsant effect was comparable to that of the positive control picrotoxin (Ward et al, 2017).…”

“…In addition, MDI-222 did not bind a panel of 70 different receptors, ion channels and transporters, further emphasising its selectivity for AMPARs. MDI-222 was the back-up compound to the lead molecule UoS12258 (Ward et al, 2017). This latter compound was also a relatively weak AMPAR PAM, having a pEC50 of 5.6 in both the Ca 2+ flux and whole-cell patch clamp assays but was much more potent that MDI-222, with, for example, the maximal potentiation in the charge transfer (i.e., area under the curve) in rat primary hippocampal neurons being 62% for MDI-222 (Table 2) and 310% for UoS12258 (Ward et al, 2017).…”

“…B. UoS12258 was proconvulsant in the MEST assay at a dose of 10 mg/kg p.o. (data not shown for clarity; Ward et al, 2017) and during dose-range finding studies caused convulsions in dogs, cynomolgus (cyno.) monkeys and rats at doses of 3, 9 and 10 mg/kg p.o., respectively.…”

“…Nevertheless, this compound serves as an example of an AMPAR PAM with a much improved safety profile relative to others within this class. The biological assay methods are described in more detail elsewhere (Ward et al, 2017). All animal studies were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals.…”

Early Identification and Intervention of Schizophrenia: Insight From Hypotheses of Glutamate Dysfunction and Oxidative Stress

“…Beneficial effects of CX516 and minocycline on cognitive domains appeared insignificant with rigorous statistical analyses (62). Newer AMPAR modulators such as UoS12258 which may possess precognitive properties deserve further studies (63).…”