Inhibitor Report for: Dehydroevodiamine

Derived from the structures of the alkaloids rutaecarpine and dehydroevodiamine (DHED), and the long-known acetylcholinesterase (AChE) inhibitor tacrine, respectively, novel compounds were synthesised, including: 13-methyl-5,8-dihydro-6H-isoquino[1,2-b]quinazolin-13-ium chloride (12), (8Z)-5,6-dihydro-8H-isoquino[1,2-b]quinazolin-8-imine (13), 5,8-dihydro-6H-isoquino[1,2-b]quinazoline (15a), 13-methyl-5,8-dihydro-6H-isoquino[1,2-b]quinazolin-13-ium chloride (16), 5,7,8,13-tetrahydroindolo [2',3':3,4]pyrido[2,1-b]quinazoline (17), and N-(2-phenylethyl)-N-[(12Z)-7,8,9,10-tetrahydroazepino [2,1-b]quinazolin-12(6H)-ylidene]amine (20), respectively. In a first step to evaluate their possible applicability for antiamnesic therapy, the inhibition of AChE and butyrylcholinesterase (BChE) were determined: compounds 13, 15a, 17, and 20 are moderate or strong inhibitors of ChE, the latter two compounds show a 10-fold higher affinity to BChE. Compound 12 is a moderate inhibitor of AChE showing selectivity towards this enzyme.

Dehydroevodiamine has been reported to have anticholinesterase activity and an anti-amnesic effect. This study examined the effects of dehydroevodiamine on scopolamine- and beta-amyloid peptide-(25--35)-induced amnesia in mice, using a step-through passive avoidance test. Similarly to the cholinesterase inhibitor, physostigmine (0.03--0.3 mg/kg, i.p.), dehydroevodiamine (0.75--12.0 mg/kg, i.p.) administered 30 min before the training trial, immediately after the training trial, and 30 min before the retention test significantly improved scopolamine- and beta-amyloid peptide-(25--35)-induced amnesia. In beta-amyloid peptide-(25--35)-induced amnesia, the rank order of anti-amnesic potency in these three administration schedules for dehydroevodiamine was different from that for physostigmine. Furthermore, dehydroevodiamine was more potent to improve beta-amyloid peptide-(25--35)-induced amnesia than scopolamine-induced amnesia when administered before the training trial. These results suggested that dehydroevodiamine may have an action other than that of an anticholinesterase and may be a novel and effective ligand for improvement of beta-amyloid type amnesia.

To find a new compound with antiamnesic activity, we screened 29 natural products for their abilities to inhibit acetylcholinesterase and reverse scopolamine-induced amnesia. Among the plants tested Evodia rutaecarpa Bentham showed a strong inhibitory effect on acetylcholinesterase in vitro and an anti-amnesic effect in vivo. By sequential fractionation of E. rutaecarpa, the active component was finally identified as dehydroevodiamine hydrochloride (DHED). DHED inhibited acetylcholinesterase activity in a dose-dependent and non-competitive manner. The IC50 value of DHED is 37.8 microM. A single administration of DHED to rats (6.25 mg/kg) significantly reversed the scopolamine-induced memory impairment in a passive avoidance test. The antiamnesic effect of DHED was more potent than that of tacrine which is the only drug for Alzheimer's disease approved by FDA. This potent antiamnesic effect of DHED was thought to be due to the combined effects of acetylcholinesterase inhibition and the known cerebral blood flow enhancement. These results indicate that DHED has novel anti-cholinesterase and antiamnesic activities and might have therapeutic potential in various disorders including Alzheimer's disease.