SUVN‐I7016031: A Novel M1‐receptor Positive Allosteric Modulator (M1‐PAM) for the treatment of Parkinson's Disease Associated Dementia

Abstract

AbstractBackgroundParkinson's disease (PD) patients experience progressive cognitive decline over the time and as the disease progresses. Drug‐induced Parkinsonism (DIP) is the second‐most‐common etiology of parkinsonism in the elderly after Parkinson's disease. DIP is indistinguishable from pathological PD as the symptoms are similar for both conditions. Haloperidol is a classical antipsychotic, known for its propensity to cause parkinsonism, which can be accompanied with the cognitive impairment, due to the blockade of striatal dopamine D2 receptors and further the downstream antagonism of M1 receptors in the signaling cascade. Therapeutic potential of SUVN‐I7016031 was evaluated in an animal model reflecting PD associated dementia.MethodHaloperidol was supplied in water feeder bottles at 2 mg/kg, p.o. to induce PD associated dementia. Following one week of haloperidol supplementation, treatment with either SUVN‐I7016031 (0.3, 1, 3 and 10 mg/kg, p.o.) or rivastigmine (0.3 mg/kg, s.c.) was began and the treatments were continued up to 37 days. Social recognition task (SRT) was conducted on day‐13 and day‐37. In SRT, familiarization and recognition trials were conducted with a trial delay of 30 min. Social investigation time by adult rat with either familiar or novel juvenile rat was assessed during recognition trial and compared, along with discriminative index. Statistical analysis is carried out using GraphPad Prism software (Version 7.02).ResultAnimals treated with haloperidol did not discriminate the novel juvenile from the familiar juvenile and showed cognitive impairment on day‐13 and day‐37. Rivastigmine reversed haloperidol‐induced PD dementia on day‐13 and day‐37. SUVN‐I7016031 at 10 mg/kg, p.o., reversed haloperidol‐induced PD dementia on day‐13 of testing. However, on day‐37, SUVN‐I7016031 reversed haloperidol‐induced PD dementia at 1, 3 and 10 mg/kg, p.o. which resulted in dose‐dependent positive efficacy. Further, rivastigmine and SUVN‐I7016031 treatment also resulted in significant improvement of discriminative index relative to haloperidol control on day‐37. Effects observed with SUVN‐I7016031 are more prominent on day‐37 relative to day‐13.ConclusionSUVN‐I7016031 showed positive efficacy in an animal model reflecting PD associated dementia, which could be a future promising therapeutic strategy in improving health related quality of life (hQOL) in PD patients.