Aaptamine – a dual acetyl – and butyrylcholinesterase inhibitor as potential anti-Alzheimer’s disease agent

Abstract

Context Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are promising therapeutic targets for AD. Objective To evaluate the inhibitory effects of aaptamine on two cholinesterases and investigate the in vivo therapeutic effect on AD in a zebrafish model. Materials and methods Aaptamine was isolated from the sponge Aaptos suberitoides Brøndsted (Suberitidae). Enzyme inhibition, kinetic analysis, surface plasmon resonance (SPR) and molecular docking assays were used to determine its inhibitory effect on AChE and BuChE in vitro . Zebrafish were divided into six groups: control, model, 8 μM donepezil, 5 , 10 and 20 μM aaptamine. After three days of drug treatment, the behaviour assay was performed. Results The IC 50 values of aaptamine towards AChE and BuChE were 16.0 and 4.6 μM. And aaptamine directly inhibited the two cholinesterases in the mixed inhibition type, with K i values of 6.96 ± 0.04 and 6.35 ± 0.02 μM, with K d values of 87.6 and 10.7 μM. Besides, aaptamine interacts with the crucial anionic sites of AChE and BuChE. In vivo studies indicated that the dyskinesia recovery rates of 5 , 10 and 20 μM aaptamine group were 34.8, 58.8 and 60.0%, respectively, and that of donepezil was 63.7%. Discussion and conclusions Aaptamine showed great potential to exert its anti-AD effects by directly inhibiting the activities of AChE and BuChE. Therefore, this study identified a novel medicinal application of aaptamine and provided a new structural scaffold for the development of anti-AD drugs.

Marine natural products

“…468 Promiscuous alkaloid aaptamine is a dual inhibitor of both acetyl- and butyryl-cholinesterase and therefore has potential as an Alzheimer's disease therapeutic lead. 469 HTS of 300 marine invertebrate extracts from Australia has revealed that the known guanidine-based, plant growth promoter asterubine binds to α-synuclein, therefore making it a lead for Parkinson's disease; asterubine structurally resembles the β-amyloid aggregation inhibitors drugs tramiprosate and ALZ-801. 470 The same HTS campaign also identified (+)-aerothionin-1 and -2 as α-synuclein inhibitors; interestingly both inhibit protein aggregation but while (+)-aerothionin-1 is toxic to dopaminergic neuronal cells, −2 is not.…”

Discovery of Hydrazone Scaffolds as Potent and Selective Multitarget‐Directed Ligands for the Treatment of Neurodegenerative Disorders

“…MAOs are membrane bounded and flavin adenine dinucleotide (FAD) dependent enzymes associated with outer membrane of mitochondria found in glial [14] and neuronal cells, [15] which belong to proteaceous family containing flavin amine oxidases. These are responsible for the degradation of chemical messengers (neurotransmitters) like dopamine, 5‐HT (serotonin), adrenalin, noradrenalin and deamination of phenylisopropylamine [6,16] . These are also present in different cells but more prominently in brain and liver cells [17] .…”

“…[5] Serine hydrolases containing two important enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are generally known as cholinesterases (ChEs). [6] Both enzymes are different in their substrate selectivity. [7] Acetylcholinesterase hydrolyzes the acetylcholine into choline and acetate.…”

“…These are responsible for the degradation of chemical messengers (neurotransmitters) like dopamine, 5-HT (serotonin), adrenalin, noradrenalin and deamination of phenylisopropylamine. [6,16] These are also present in different cells but more prominently in brain and liver cells. [17] Monoamine oxidase is present in two isozymes (MAO-A and MAO-B), exhibiting distinct specificity of substrate, inhibitors sensitivity and arrangement of amino acid residues.…”

Oxidative Cyclization at ortho-Position of Phenol: Improved Total Synthesis of 3-(Phenethylamino)demethyl(oxy)aaptamine

“…Aaptamines are a class of alkaloids derived from marine sponges, particularly from Aaptos sp., with cytotoxic, antifungal, and antibacterial activities [ 1 , 2 , 3 ]. Recent studies disclosed the potential of aaptamine as therapeutic agent for neuropathic pain or Alzheimer’s disease [ 4 , 5 ], enhancing the importance of the compound. Demethyl(oxy)aaptamine ( 1 in Figure 1 ) [ 6 ], an oxidized aaptamine derivative, is also known for its interesting biological activities.…”