Pharmacology of selective acetylcholinesterase inhibitors: implications for use in Alzheimer's disease

• Published in: European journal of pharmacology Vol. 486; no. 1; pp. 9 - 17
• Main Authors: Liston, Dane R., Nielsen, Jann A., Villalobos, Anabella, Chapin, Douglas, Jones, Shawn B., Hubbard, Sean T., Shalaby, Ismail A., Ramirez, Andres, Nason, Deane, White, W.Frost
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 13-02-2004; Elsevier
• Subjects: Acetylcholine - metabolism; Acetylcholinesterase; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer's disease; Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Butyrylcholinesterase; Butyrylcholinesterase - blood; Cholinesterase inhibitor; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Donepezil; Dose-Response Relationship, Drug; Humans; Indans - pharmacology; Male; Medical sciences; Mice; Pharmacology. Drug treatments; Physostigmine - analogs & derivatives; Physostigmine - pharmacology; Piperidines - pharmacology; Rats; Rats, Sprague-Dawley; Tacrine - pharmacology; Acetylcholinesterase; Butyrylcholinesterase; Alzheimer's disease; Cholinesterase inhibitor; Nervous system diseases; Enzyme; Alzheimer disease; Central nervous system disease; Hydrolases; Esterases; Degenerative disease; Carboxylic ester hydrolases; Cerebral disorder
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2003.11.080

Cholinesterase inhibitors vary in their selectivity for acetylcholinesterase versus butyrylcholinesterase. We examined several cholinesterase inhibitors and assessed the relative role of acetylcholinesterase versus butyrylcholinesterase inhibition in central and peripheral responses to these medications. Donepezil and icopezil are highly selective for acetylcholinesterase, whereas tacrine and heptylphysostigmine demonstrated greater potency for butyrylcholinesterase over acetylcholinesterase. All four compounds increased acetylcholine levels in mouse brains. Dose–response curves for tremor (central effect) and salivation (peripheral effect) showed that donepezil and icopezil possess a more favourable therapeutic index than the nonselective inhibitors, tacrine and heptylphysostigmine. Co-administration of the selective butyrylcholinesterase inhibitor tetraisopropylpyrophosphoramide (iso-OMPA) potentiated peripheral, but not central, effects of the selective acetylcholinesterase inhibitor icopezil. The improved therapeutic index observed in mice with icopezil is due to a high degree of selectivity for acetylcholinesterase versus butyrylcholinesterase, suggesting that high selectivity for acetylcholinesterase may contribute to the clinically favourable tolerability profile of agents such as donepezil in Alzheimer's disease patients.