Schistosoma mansoni: species-selective response to N-chloroethyl-acetylcholine derivatives.
Three new acetylcholine mustard analogs were tested on schistosome and vertebrate neuromuscular preparations. These compounds extend a previously reported structure-activity series. The new compounds investigated include isopropyl-, cyclohexyl-, and benzyl-2-acetoxyethyl-2'-chloroethylamine (PrM, ChM, and BzM). In schistosome motor activity studies, all of the compounds caused irreversible reductions in the activity of Schistosoma mansoni after 1 hr exposure followed by 19 hr in drug-free medium. Under nonlethal conditions of dosage and exposure time, all compounds blocked carbachol-induced paralysis, indicating a possible action at schistosome cholinergic sites. All the compounds also reduced the labeling of schistosomes by dimethylaminonapthalene-5-sulfonamidoethyl dimethylamine hydrochloride (DDNS), a fluorescent ACh analog. In isolated vertebrate tissue experiments. PrM and ChM had slight agonist activity in the guinea pig ileum, and only PrM had agonist activity in the frog rectus abdominis preparation. PrM and BzM were found to antagonize ACh responses in the guinea pig ileum. Exposure of vertebrate tissues for 1 hr to high concentrations of ChM caused no long-lasting inhibition of ACh, pilocarpine, and serotonin (5HT) responses. Histamine responses were slightly reduced from control. Following 1 hr exposure of vertebrate tissues to PrM, initial reductions in all responses were seen, followed by recoveries to near control. BzM treatment, however, reduced all responses far below control; the tissues did not recover even after washing for 2 hr. It is concluded that ChM and, to a lesser extent, PrM, had a greater effect on schistosomes than on vertebrate tissues. BzM did not display species selectivity in this favorable direction.
D000109:Acetylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D009068:Movement / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects*; D010862:Pilocarpine / Q000494:pharmacology; D011898:Ranidae; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D013045:Species Specificity; D013329:Structure-Activity Relationship
D010862:Pilocarpine; D012701:Serotonin; D006632:Histamine; C038856:benzyl-2-acetoxyethyl-2'-chloroethylamine; C038855:isopropyl-2-acetoxyethyl-2'-chloroethylamine; C038857:cyclohexyl-2-acetoxyethyl-2'-chloroethylamine; D002217:Carbachol; D000109:Acetylcholine