Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders

摘要: The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role regulating neuroinflammatory processes, activation of may produce neuroprotective effects diseases. Novel small molecule modulators ADRB1, engineered to be highly brain permeable functionally selective for G protein partial agonistic activity, could have tremendous value both as pharmacological tools potential lead molecules further preclinical development. present study describes our ongoing efforts toward discovery agonists AD disorders, which has led identification STD-101-D1. As agonist STD-101-D1 produces activity on signaling EC50 low nanomolar range, but engages very little beta-arrestin recruitment compared unbiased isoproterenol. also inhibits tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) vitro vivo, shows high penetration. Other than role, this newly identified, selective, invaluable research tool mechanisms protein-coupled signal transduction.