title: Inhibitory activity of camptothecin derivatives against acetylcholinesterase in dogs and their binding activity to acetylcholine receptors in rats.
abstract: A camptothecin derivative, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), shows a potent antitumour activity in experimental tumour models and in clinical trials. However, CPT-11 induced early diarrhoea and vomiting at high dose levels in clinical studies and showed an acetylcholine-like action on the guinea-pig ileum and trachea. In the present study, we investigated the activities of camptothecin derivatives in inhibiting acetylcholinesterase (AChE) and in binding to muscarinic acetylcholine receptors (AChR). CPT-11 inhibited AChE and binding of the specific ligand to AChR with respective 50% inhibition concentrations of 0.2 and 5 microM. These inhibitions were induced by camptothecin derivatives having an amino group at the C-10 position (or the C-4 position of hexacyclic derivatives), but were not or were only slightly induced by the others. Early defecation and vomiting in dogs were observed after intravenous injection of DU-6596 and DU-6888, two hexacyclic derivatives having the aminomethyl group at the C-4 position, and of CPT-11. DU-6174, however, which has a hydroxy group at this position, induced no early defecation and little vomiting. Plasma concentrations of CPT-11, DU-6596 and DU-6888 after intravenous treatment at doses causing such early adverse effects were maintained for 1 h or longer at levels sufficient to inhibit AChE. These results suggest that the inhibition of AChE by camptothecin derivatives with an amino group at the C-10 position (or the C-4 position) relates to the early defecation or diarrhoea and vomiting.
authors.affiliation: Exploratory Research Laboratories I, Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawato
authors.forename: M
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: K
authors.initials: K
authors.lastname: Akahane
authors.forename: Y
authors.initials: Y
authors.lastname: Tsutomi
authors.forename: Y
authors.initials: Y
authors.lastname: Hirota
authors.forename: H
authors.initials: H
authors.lastname: Kuga
authors.forename: W
authors.initials: W
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Hakusui
authors.forename: K
authors.initials: K
authors.lastname: Sato
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D003672:Defecation / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced; D004285:Dogs; D007275:Injections, Intravenous; D000077146:Irinotecan; D008297:Male; D051381:Rats; D011950:Receptors, Cholinergic / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors; D014839:Vomiting / Q000139:chemically induced
chemical_list: D002800:Cholinesterase Inhibitors; D011950:Receptors, Cholinergic; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin