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

Abstract

Purpose: There is considerable interest in positive allosteric modulators (PAMs) of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) subtype of ionotropic glutamate receptors as therapeutic agents for a range of cognitive and mood disorders. However, the challenge is to increase AMPA receptor (AMPAR) function sufficient to enhance cognitive function but not to the extent that there are mechanism-related pro-convulsant or convulsant side effects. In this present study, we report the preclinical pharmacology data for MDI-222, an AMPAR PAM which enhances cognition but has a much reduced side-effect (i.e. convulsant) liability relative to other molecules of this mechanism. Methods: The pharmacological effects of MDI-222 were characterised in in vitro and in vivo preclinical electrophysiology, efficacy (cognition), side-effect (pro-convulsant/convulsant), tolerability and toxicity assays. Results: We demonstrate that MDI-222 is an AMPAR PAM, since it enhanced AMPAR function in vitro at human (hGluA1-4) and rat (rGluA2) homomeric receptors, and potentiated hetero-oligomeric AMPARs in rat neurons. MDI-222 enhanced electrically evoked AMPAR-mediated synaptic transmission in the anaesthetised rat at 10 mg/kg (administered intravenously) and did not significantly lower the seizure threshold in the pro-convulsant maximal electroshock threshold test (MEST) at any dose tested up to a maximum of 30 mg/kg (administered by oral gavage (p.o.)). MDI-222 reversed a delay-induced deficit in novel object recognition (NOR) in rats with a minimum effective dose (MED) of 0.3 mg/kg (p.o.) following acute administration, which was reduced to 0.1 mg/kg following sub-chronic administration, and improved passive avoidance performance in scopolamine-impaired rats with a MED of 10 mg/kg p.o. On the other hand, MDI-222 was not pro-convulsant in the MEST, resulting in a therapeutic window between plasma concentrations that enhanced cognitive performance and those associated with mechanism-related side effects of ⩾1000-fold. Unfortunately, despite the excellent preclinical profile of this compound, further development had to be halted due to non-mechanism-related issues. Conclusions: We conclude that MDI-222 is an AMPAR PAM which enhances cognitive performance in rats and has a significantly improved safety profile in preclinical species.

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…42). The functional actions of new agents on AMPA receptors so far have been similar to existing PAMs (Partin, 2015;Bretin et al, 2017;Brogi et al, 2019;Ward et al, 2020).…”

Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

“…However, to select the best candidate, we examined the safety profile of the new compounds in vivo by determining their possible pro-convulsant effect or induction of hypothermia resulting from a massive per os drug administration in NMRI mice (30 mg/kg and 100 mg/kg). Indeed, a major concern with AMPAR PAMs is seizure induction at high doses resulting from an excessive stimulation of the glutamatergic neurotransmission in the CNS [42,43]. Unfortunately, compound 32 induced hypothermia at 30 mg/kg per os in NMRI mice, while compound 36 was remarkably safe up to 100 mg/kg (no hypothermia and convulsions; see Fig.…”

Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

“…However, to select the best candidate, we examined the safety profile of the new compounds in vivo by determining their possible pro-convulsant effect or induction of hypothermia resulting from a massive per os drug administration in NMRI mice (30 mg/kg and 100 mg/kg). Indeed, a major concern with AMPAR PAMs is seizure induction at high doses resulting from an excessive stimulation of the glutamatergic neurotransmission in the CNS [41,42]. Unfortunately, compound 32 induced hypothermia at 30 mg/kg per os in NMRI mice, while compound 36 was remarkably safe up to 100 mg/kg (no hypothermia and convulsions; see Figure 4).…”