title: Acetylcholinesterase inhibition and anti-soman efficacy of homologs of physostigmine.
abstract: Inhibition of acetylcholinesterase (AChE) activity by physostigmine (PHY) is reversible due to spontaneous decarbamylation. Physostigmine has been shown to be effective as a pretreatment against potent anticholinesterase poisons (e.g., soman) in experimental animals, yet it is short acting and causes undesirable side effects in mammals. The two-fold purpose of this study was 1) to determine whether extension of the N-substituted alkyl chain (N-SAC) of PHY from N-methyl to N-ethyl (I), N-propyl (II), N-isopropyl (III), N-butyl (IV) or N-heptyl (V) affects anti-AChE potency and spontaneous decarbamylation of inhibited AChE of guinea pig blood in vitro and in vivo, and 2) to see whether chain extension affects efficacy as pretreatment in poisoning by soman. The in vitro AChE inhibition studies were done using whole blood incubated at 37 degrees C for 30 min. All 5 homologs possessed anti-AChE activity with I50s ranging from 1.1 to 27.6 x 10(-7)M; compound III was the least potent in vitro and in vivo. Lengthening of the N-SAC of PHY markedly extended the duration of anti-AChE activity when compared to PHY, but rendered the modified compounds ineffective as pretreatments against soman. These data support the premise that the decrease in decarbamylation rates observed upon extending the N-SAC of PHY is responsible for the loss of effectiveness of pretreatment regimens against soman. Perhaps, these homologs of PHY may have potential use in instances where sustained action of acetylcholine is required at cholinergic junctions because of disease conditions or drug overdosage.
authors.affiliation: US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
authors.forename: L W
authors.initials: LW
authors.lastname: Harris
authors.forename: D R
authors.initials: DR
authors.lastname: Anderson
authors.forename: A M
authors.initials: AM
authors.lastname: Pastelak
authors.forename: S L
authors.initials: SL
authors.lastname: Bowersox
authors.forename: B A
authors.initials: BA
authors.lastname: Vanderpool
authors.forename: W J
authors.initials: WJ
authors.lastname: Lennox
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D001285:Atropine / Q000627:therapeutic use*; D002265:Carboxylic Ester Hydrolases / Q000172:deficiency*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D005260:Female; D006168:Guinea Pigs; D008297:Male; D010830:Physostigmine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D012999:Soman / Q000037:antagonists & inhibitors* / Q000506:poisoning; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D001285:Atropine; D012999:Soman; D010830:Physostigmine; D002265:Carboxylic Ester Hydrolases; C023201:tropinesterase; D000110:Acetylcholinesterase