INHIBITORY ACTIVITY OF CAMPTOTHECIN DERIVATIVES AGAINST ACETYLCHOLINESTERASE IN DOGS AND THEIR BINDING-ACTIVITY TO ACETYLCHOLINE-RECEPTORS IN RATS

A camptothecin derivative, 1-piperidino)-1-piperidino]carbonyloxycampt othecin (CPT-11), shows a potent antitumour activity in experimental t umour models and in clinical trials. However, CPT-11 induced early dia rrhoea 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 deri vatives in inhibiting acetylcholinesterase (AChE) and in binding to mu scarinic acetylcholine receptors (AChR). CPT-11 inhibited AChE and bin ding of the specific ligand to AChR with respective 50% inhibition con centrations of 0.2 and 5 muM. These inhibitions were induced by campto thecin derivatives having an amino group at the C-10 position (or the C-4 position of hexacyclic derivatives), but were not or were only sli ghtly induced by the others. Early defecation and vomiting in dogs wer e observed after intravenous injection of DU-6596 and DU-6888, two hex acyclic derivatives having the aminomethyl group at the C-4 position, and of CPT-11. DU-6174, however, which has a hydroxy group at this pos ition, induced no early defecation and little vomiting. Plasma concent rations of CPT-11, DU-6596 and DU-6888 after intravenous treatment at doses causing such early adverse effects were maintained for 1 h or lo nger 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 defec ation or diarrhoea and vomiting.