SUVN‐I6107: Efficacy and safety assessments of a true muscarinic M1‐positive allosteric modulator for the treatment of dementia

Abstract

AbstractBackgroundM1 muscarinic agonist has failed in time past in clinical trials to treat dementia observed in the elderly on account of its side effect profile. In the current investigation, we evaluated efficacy and safety of SUVN‐I6107 an M1‐positive allosteric modulator (PAM) in various animal models and compared it with earlier M1‐PAMs.MethodIn‐vitro characterization of SUVN‐I6107 was done using the reporter gene assay and radio‐ligand binding assay at muscarinic receptors. SUVN‐I6107 was evaluated for efficacy and compared with earlier M1‐PAMs. An extensive characterization of SUVN‐I6107 was carried out to understand the margin of safety in various animal models. Earlier M1‐PAMs were also assessed as a comparator.ResultBased on the reporter gene assay and radio‐ligand binding studies, SUVN‐I6107 was characterized as a M1‐PAM with no agonist like activity. No notable effects were observed at other muscarinic receptors subtypes (M2, M3, M4 and M5). SUVN‐I6107 was found to reverse time, and scopolamine induced memory deficits in various animal models of cognition. SUVN‐I6107 did not show any spike potentiation effect in agonist mode of testing (slice electrophysiology), which indicates that it has no M1 agonist like effect. Cholinergic signs were not observed at doses which were efficacious in the cognition studies. Cholinergic signs were observed several folds higher than the efficacious doses. SUVN‐I6107 was found to be safer than the earlier M1‐PAMs sans several of the characteristic side effect profile.ConclusionDoses of SUVN‐I6107 which exhibited procognitive activity were several folds lower than the doses where cholinergic signs were seen in animals. Earlier M1‐PAMs did not have a wide margin of safety in comparison to the efficacious dose.