Changes in cholinesterase levels and the resulting depletion of the neurotransmitter acetylcholine have been found in patients with Alzheimer’s disease and suggested to contribute to the symptoms of neurodegenerative disease. Of the two major classes of cholinesterases, acetylcholinesterase (AChE) activity decreases or remains unchanged, but butyrylcholinesterase (BChE) activity increases. To reduce depletion of acetylcholine, BChE-specific inhibitors have been evaluated as potential therapeutics to manage the progression of neurodegenerative diseases. Based on previous studies that used compounds containing aromatic and carbamate groups as inhibitors, we postulated 9-fluorenylmethoxycarbonyl (Fmoc)-amino acids may provide an attractive starting point to develop a new class of inhibitors, as the amino acid analogs contain aromatic and carbamate groups and can be readily varied. We identified several Fmoc-amino acids that selectively inhibit BChE including Fmoc-Leu-O-, Fmoc-Trp-O-, and Fmoc-Lys-O- with inhibition constants (KI values) of 115, 150, 193 mM for Fmoc-Leu-O-, Fmoc-Lys-O-, and Fmoc-Trp-O- respectively. The Fmoc group was important for inhibition, as carboxylbenzyl (Cbz) analogs were less potent inhibitors. Inclusion of a t-butoxycarbonyl (Boc) group in the Trp side chain led to best inhibitor with a KI value of 20 mM. Calculations of van der Waals volumes suggested the compounds are too large to fit in the smaller active site gorge of AChE but can be accommodated by BChE, providing for selectivity. As a wealth of chemistry is available to synthesize modified amino acids and peptides, we are currently evaluating additional Fmoc-amino acid analogs and peptides bearing these analogs to identify more potent BChE-selective inhibitors.

Evaluating Fmoc-amino acids as butyrylcholinesterase inhibitors

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.