A series of metal complexes containing Phenanthroline scaffold [ML] (L-1,10-Phenanthroline derivative comprises conjugated aromatic core and selenol group); M = Cu(II), Zn(II), Co(II) and Zn(II) ions were designed and synthesised to obtain effective anti-cholinesterase efficiencies of metal chelates. Analytical and spectroscopic studies were used to determine the structural features. An octahedral structure with moderate distortion was attributed to the above metal chelates based on spectroscopic data. The distorted octahedral geometry of copper(II) complex to DNA (K(b) = 4.05 x 10(5) M(-1)) is stronger than that of ethidium bromide (EB) to DNA (K(b) = 3.2 x 10(5) M(-1)), other metal complexes, respectively. The synthesised 1,10-Phenanthroline derivative had the best inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase, with IC(50) values of 0.45 and 3.6 M, respectively, which were lower than the reference molecules. As a result, nitrogen-containing heterocyclic compounds (H(2)L) showed significant inhibitory profiles against the metabolic enzymes. Therefore, we believe that these experimental results may contribute to the development of new drug molecules particularly in the treatment of neurological disorders including glaucoma, Alzheimer's disease (AD) and diabetes. Docking, AChE and BuChE inhibition activities results revealed that ligand may be used for AD. The prepared 1,10-phenanthroline analogue, which has a high selectivity for AChE, may be studied further to find potential candidates for treating early-stage Alzheimer's symptoms.Communicated by Ramaswamy H. Sarma.
After the inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents, a dealkylation reaction of the phosphylated serine, referred to as aging, can occur. When aged, known reactivators of OP-inhibited AChE are no longer effective. Realkylation of aged AChE may provide a route to reversing aging. We designed and synthesized a library of quinone methide precursors (QMPs) as proposed realkylators of aged AChE. Our lead compound (C8) from an in vitro screen successfully resurrected 32.7 and 20.4% of the activity of methylphosphonate-aged and isopropyl phosphate-aged electric-eel AChE, respectively, after 4 days. C8 displays properties of both resurrection (recovery from the aged to the native state) and reactivation (recovery from the inhibited to the native state). Resurrection of methylphosphonate-aged AChE by C8 was significantly pH-dependent, recovering 21% of activity at 4 mM and pH 9 after only 1 day. C8 is also effective against isopropyl phosphate-aged human AChE.
Title: pH-Responsive Fluorescence Enhancement in Graphene Oxide-Naphthalimide Nanoconjugates: A Fluorescence Turn-On Sensor for Acetylcholine Mangalath S, Abraham S, Joseph J Ref: Chemistry, 23:11404, 2017 : PubMed
A pH-sensitive, fluorescence "turn-on" sensor based on a graphene oxide-naphthalimide (GO-NI) nanoconjugate for the detection of acetylcholine (ACh) by monitoring the enzymatic activity of acetylcholinesterase (AChE) in aqueous solution is reported. These nanoconjugates were synthesized by covalently anchoring picolyl-substituted NI derivatives on the GO/reduced GO surface through a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide coupling strategy, and the morphological and photophysical properties were studied in detail. Synergistic effects of pi-pi interactions between GO and the NI chromophore, and efficient photoinduced electron- and energy-transfer processes, were responsible for the strong quenching of fluorescence of these nanoconjugates, which were perturbed under acidic pH conditions, leading to significant enhancement of fluorescence emission. This nanoconjugate was successfully employed for the efficient sensing of pH changes caused by the enzymatic activity of AChE, thereby demonstrating its utility as a fluorescence turn-on sensor for ACh in the neurophysiological range.
The functional role of releasable Zn2+ in the central nervous system remains unknown. Here we show that zinc transporter 3 (ZnT-3), which maintains a high concentration of Zn2+ in synaptic vesicles and serves as a marker for zinc-containing neurons, is enriched in the lateral nucleus of the amygdala and in the temporal area 3 of the auditory cortex, an area that conveys information about the auditory conditioned stimulus to the lateral nucleus of the amygdala, but not in other conditioned stimulus areas located in the auditory thalamus. Using whole-cell recordings from amygdala slices, we demonstrated that activity-dependent release of chelatable Zn2+ is required for the induction of spike timing-dependent long-term potentiation in cortical input to the amygdala implicated in fear learning. Our data indicate that synaptically released Zn2+ enables long-term potentiation at the cortico-amygdala synapses by depressing feed-forward GABAergic inhibition of principal neurons. This regulatory mechanism, implicating pathway-dependent release of Zn2+, may serve an essential control function in assuring spatial specificity of long-lasting synaptic modifications in the neural circuit of a learned behavior.
