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Another approach to modulate NNMT involves bisubstrate inhibitors, which are designed to resemble both the substrate (NAM) and the cofactor (SAM)

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Notably, in contrast to 23 (HA08), a structurally very similar epimer (HA09) which differs only with regard to one stereogenic center and exhibiting a 100-fold lower affinity to IRAP did not affect spine morphology, indicating a correlation between the capacity to inhibit IRAP and a positive impact on DSD and spine morphology