P4‐222: Long‐term sertraline treatment increases expression and phosphorilation of glycogen synthase kinase‐3B in platelets of patients with late‐life major depression

Abstract

the frontal cortex and hippocampus. 5-HT 4 receptor partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders via modulation of amyloid precursor protein (APP) derived peptides, amyloid beta (Ab) and soluble amyloid precursor protein alpha (sAPPa) in the CNS. Our effective lead optimization has resulted into SUVN-D1108121 as a lead like molecule from our CNS discovery programme, exhibited pro-cognitive properties in preclinical animal models and increased neurotransmitters involved in cognition. Methods: The fuctional activity of the SUVN-D1108121 was tested in adenylyl cyclase assay in CHO cells expressing human 5HT 4(e) receptor and Ki value was determined at novascreen in radioligand binding study using 5-HT 4 membrane. In-vitro metabolism studies (metabolic stability, CYP inhibition and protein binding), pharmacokinetic and brain penetration profile were evaluated in the preclinical species.In-vivo striatal 5-HT 4 receptor occupancy was measured in rats using LC-MS/MS based tracer analysis. Modulation of cortical sAPPa in mice and CSF amyloidb protein levels in rats were evaluated. Results: SUVN-1108121 exhibited partial agonist activity with an EC 50 value of 0.09 nM when tested for functional activity in adenylyl cyclase assay and Ki value of 0.15 nM in radioligand binding studies. SUVN-D1108121 is found to be stable in human in-vitro liver preparations with no drug interaction potential.SUVN-D1108121 had good oral bioavailability and efficiently penetrate the CNS with good free concentrations at the target site. SUVN-D1108121 showed dose dependent increase in striatal receptor occupancy at tested dose levels. A significant increase in the cortical sAPPa levels was observed i.e. 39, 41, 46 & 66 % at 0.3, 1, 3 and 10 mg/kg, s.c. respectively. A dose dependent decrease in CSF amyloid-b protein levels was observed in non-transgenic animal model. Conclusions: The preclinical data suggests that SUVN-D1108121 is a novel potent, selective, orally bioavailable and efficacious 5-HT 4 receptor partial agonist that holds promise for the management of hallmark symptomatologies observed in Alzheimer’s disease. The compound is currently under further investigations to qualify as a clinical candidate.