Brain-penetrant LSD1 inhibitors can block memory consolidation

摘要: Modulation of histone modifications in the brain may represent a new mechanism for disorder therapy. Post-translational histones regulate gene expression, affecting major cellular processes such as proliferation, differentiation, and function. An important enzyme involved one these is lysine specific demethylase 1 (LSD1). This flavin-dependent exhibits homology to amine oxidases. Parnate (2-phenylcyclopropylamine (2-PCPA); tranylcypromine) potent inhibitor monoamine oxidases derivatives 2-PCPA have been used development selective LSD1 inhibitors based on ability form covalent adducts with flavin adenine dinucleotide (FAD). Here we report synthesis vitro characterization that bond covalently FAD. The two most were demonstrate penetration when administered systemically rodents. First, radiosynthesis positron-emitting analog was obtain preliminary bio-distribution data whole time-activity curves. Second, this series capable producing cognitive effect mouse model. By using memory formation paradigm, novel object recognition, show inhibition can abolish long-term without short-term memory, providing further evidence importance reversible methylation function nervous system.