SUVN‐I6107: A True Positive Allosteric Modulator (PAM) at Muscarinic M1 Receptors for the Treatment of Cognitive Disorders

Abstract

AbstractBackgroundMuscarinic acetylcholine receptors belong to the family of G‐protein coupled receptors and are expressed widely throughout the body. Muscarinic receptors have been implicated in the pathophysiology of various central nervous system disorders. M1 subtype of muscarinic receptors play a crucial role in cognition, attention, and sensory processing. The discovery and development of selective ligands targeting M1 subtype have been unsuccessful largely due to the highly conservative orthosteric binding site. Thus, ligands that selectively bind to a less conserved allosteric site of M1 receptors and positively modulate the orthosteric site may circumvent the selectivity issues as posed by orthosteric ligands.MethodSUVN‐I6107 is a clinical candidate identified from the M1 positive allosteric modulator (M1‐PAM) program. The effects of SUVN‐I6107 on the allosteric site of the M1 receptor were evaluated using the reporter gene assay. Binding liability towards orthosteric sites across all the muscarinic receptor subtypes was also evaluated. The pharmacokinetic properties of SUVN‐I6107 were studied both in rodent and non‐rodent species. The pro‐cognitive potential of SUVN‐I6107 was evaluated in diverse animal models of learning and memory. The safety of SUVN‐I6107 was assessed using various in vitro and in vivo systems.ResultSUVN‐I6107 was found to be a selective M1‐PAM with no agonistic activity at Muscarinic M1 and selective across other muscarinic receptor subtypes. SUVN‐I6107 showed good oral bioavailability in rat, dog and monkey. It also has excellent brain penetration with adequate protein free fraction. SUVN‐I6107 reversed the delay‐induced memory deficit in object recognition task. It also attenuated scopolamine‐induced memory deficit in the object recognition as well as contextual fear conditioning task. SUVN‐I6107 enhanced cerebral blood flow, potentiated the effects of donepezil and promoted non‐amyloidogenic amyloid precursor protein processing in rats. SUVN‐I6107 is devoid of side effects associated with the stimulation of the cholinergic system. SUVN‐I6107 was found to be safe in the safety pharmacology and phase‐1 enabling animal toxicity studies.ConclusionSUVN‐I6107, a novel, potent and selective M1‐PAM demonstrated efficacy in animal models and devoid of cholinergic side effects