Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties

Standardized extract of Withania somnifera (Ashwagandha) markedly offsets rotenone-induced locomotor deficits, oxidative impairments and neurotoxicity in Drosophila melanogaster

“…Fig. 7 Modulatory effect of Withania somnifera powder (WS, 0.01 and 0.05 %, 5 days) on ROT (500 μM, 5 days) induced depletion in the levels of dopamine in the whole body homogenates of adult male Drosophila melanogaster; Values are mean ± SE (n =50 flies per replicate, three such replication used for assay); Data was analyzed by One way ANOVA followed by post hoc 'Tukey' test (*p <0.05) In the present model, another important observation made by us is related to the attenuation of cholinergic function by WS per se which corroborates previous findings in which the inhibitory potential of withanolides were demonstrated in vitro (Choudhary et al 2005) and in vivo (Kumar and Kumar 2009). Interestingly, in the co-exposure paradigm, ROT induced enhancement in the activity levels of AChE and BChE were restored to normal levels by WS.…”

“…WS root extract and withanoside VI were shown to possess inhibitory action on acetylcholinesterase activity in both in vivo and in vitro (Choudhary et al 2005). Further, evidences suggest the protective effect of WS root extract and its constituents on presynaptic and post-synaptic neurons in animal models of dementia and spinal cord injury (Kuboyama et al 2005).…”

Withanolides and Related Steroids

“…Molecular docking studies indicated that all compounds are imbedded in the aromatic gorge of AChE. All these withanolides also showed dose-dependent spasmolytic and Ca 2+ antagonistic activities that may help in prolonging neuron survival and function (265). Withanoside VI (32) and withaferin A attenuated the desensitization to clonidine of smooth muscle, and this effect was related to the effect of W. somnifera on morphine tolerance and dependence (27).…”

Structural insight into the inhibition of acetylcholinesterase by 2,3,4, 5-tetrahydro-1, 5-benzothiazepines

“…We already have reported a number of new inhibitors of cholinesterase (AChE and BChE) enzymes [7 -10]. The inhibition kinetics, pharmacological profiles, molecular docking, 3D-QSAR (CoMFA and CoMSIA) studies have also been conducted for a good number of compounds [11][12][13][14][15]. Continuing our on going search for new inhibitors of therapeutically significant enzymes through highthroughput screening assays, we recently synthesized benzothiazepines 1-3, with valuable AChE inhibitory potential [16].…”