title: Pharmacology of selective acetylcholinesterase inhibitors: implications for use in Alzheimer's disease.
abstract: 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.
authors.affiliation: CNS Discovery, Pfizer Global Research and Development, Pfizer Inc., Eastern Point Road, Mailstop 8220-4016, Groton, CT 06340, USA. dane_r_liston@groton.pfizer.com
authors.forename: Dane R
authors.initials: DR
authors.lastname: Liston
authors.forename: Jann A
authors.initials: JA
authors.lastname: Nielsen
authors.forename: Anabella
authors.initials: A
authors.lastname: Villalobos
authors.forename: Douglas
authors.initials: D
authors.lastname: Chapin
authors.forename: Shawn B
authors.initials: SB
authors.lastname: Jones
authors.forename: Sean T
authors.initials: ST
authors.lastname: Hubbard
authors.forename: Ismail A
authors.initials: IA
authors.lastname: Shalaby
authors.forename: Andres
authors.initials: A
authors.lastname: Ramirez
authors.forename: Deane
authors.initials: D
authors.lastname: Nason
authors.forename: W Frost
authors.initials: WF
authors.lastname: White
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000097:blood; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007189:Indans / Q000494:pharmacology; D008297:Male; D051379:Mice; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013619:Tacrine / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D013619:Tacrine; C052450:physostigmine heptyl; D000077265:Donepezil; D010830:Physostigmine; D002091:Butyrylcholinesterase; D000109:Acetylcholine