ASS234 is a brain-penetrant and orally active multi-target small molecule (MTSM) against (acetyl & butyryl) cholinesterases (hAChE/hBuChE IC50 = 0.81/1.82 μM), monoamine oxidases (hMAO-A/B IC50 = 0.27/120 nM), histamine H3 receptor (hH3R Ki = 84.2 nM; hH4R Ki >10 μM) and sigma-1/2 receptors (hS1R/rS2R = 2.82/50.3 nM). ASS234 exhibits antioxidative and neuroprotective effects in SH-SY5Y cultures (5 μM) and demonstrates therapeutic efficacy in neurodegerative disease models in vivo via sc. (0.62 mg/kg/d mice; 5 mg/kg rats), ip. (1 mg/kg mice) or po. (1 & 10 mg/kg mice).
he multi-target enzyme inhibitor (FW = g/mol), also known as N-((5-(3- (1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N- methylprop-2-yn-1-amine, bears the MAO-inhibiting propargyl group attached to a cholinesterase-inhibiting donepezil moiety retains the ability to inhibit human acetyl- and butyryl-cholinesterases as well as monamine oxidases. With a kinact/KI value of 3 × 106 min? 1 M? 1 , ASS234 inhibition of MAO A and MAO B by ASS234 is almost as effective as clorgyline. It also forms the same N5 -adduct with the isoalloxazine ring of the FAD cofactor. The kinetic studies demonstrate that ASS234 is not only a reversible inhibitor of both acetyl and butyryl-cholinesterases with μM affinity, but is also a highly potent irreversible inhibitor of MAO A similarly to clorgyline.
