title: Inhibition of cholinesterase-associated aryl acylamidase activity by anticholinesterase agents: focus on drugs potentially effective in Alzheimer's disease.
abstract: The potency of a series of anticholinesterase (anti-ChE) agents and serotonin-related amines as inhibitors of the aryl acylamidase (AAA) activity associated with electric eel acetylcholinesterase (AChE) (EC 3.1.1.7) and horse serum butyrylcholinesterase (BuChE) (EC 3.1.1.8) was examined and compared with the potency of the same compounds as ChE inhibitors. Neostigmine, physostigmine, BW 284C51, (+/-)-huperzine A, E2020, tacrine, edrophonium and heptyl-physostigmine were, in that order, the most potent in inhibiting eel AChE-associated AAA activity, their inhibitor constant (Ki) values being in the range 0.02-0.37 microM. The rank order of the same compounds as AChE inhibitors basically paralleled that of AAA, although they were in general stronger on AChE (Ki = 0.001-0.05). The peripheral anionic site inhibitors propidium and gallamine were inactive on AChE-associated AAA. Serotonin and its derivatives were slightly stronger on AAA (Ki = 7.5-30 microM) than on AChE (Ki = 20-140 microM). Tacrine (IC50 = 0.03 microM), diisopropylfluorophosphate (IC50 = 0.04 microM), heptyl-physostigmine (IC50 = 0.11 microM), physostigmine (IC50 = 0.15 microM) and tetra-iso-propylpyrophosphoramide (iso-OMPA) (IC50 = 0.75 microM) were the most potent in inhibiting horse serum BuChE-associated AAA activity. Serotonin and related amines were very weak on BuChE-associated AAA activity. These results indicate that the inhibitory potencies of the active site anti-ChE agents on the AAA activity associated with eel AChE and horse serum BuChE are closely correlated with their action on the respective ChE. In addition, the efficacy of tacrine, E2020, heptyl-physostigmine and (+/-)-huperzine A in the treatment of Alzheimer's disease is unlikely to be related to the action of these drugs on ChE-associated AAA.
authors.affiliation: Dipartimento Di Farmacologia Preclinica E Clinica, Università Di Firenze, Florence, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Costagli
authors.forename: A
authors.initials: A
authors.lastname: Galli
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D002802:Cholinesterases / Q000378:metabolism*; D004593:Electrophorus; D006801:Humans
chemical_list: D002800:Cholinesterase Inhibitors; D002802:Cholinesterases; D000581:Amidohydrolases; C019732:aryl acylamidase