The antiproliferative and antimetastatic compound L651582 inhibits muscarinic acetylcholine receptor-stimulated calcium influx and arachidonic acid release.
L651582, a carboxyamide-amino-imidazole, was shown previously to have antiproliferative and antimetastatic properties at low micromolar concentrations; yet little is known about its cellular mechanism(s) of action. L651582 was tested for its ability to block receptor-stimulated calcium influx, arachidonic acid release, inositol phosphate and cyclic AMP (cAMP) generation. These signal transduction pathways are activated by muscarinic receptors transfected and expressed in Chinese hamster ovary cells. L651582 blocked muscarinic m5 receptor-stimulated 45Ca++ influx and release of arachidonic acid at low micromolar concentrations. Muscarinic receptor-stimulated release of arachidonic acid was shown previously to be dependent on calcium influx and not intracellular calcium release suggesting L651582 may be useful as calcium channel blocker. At low micromolar concentrations, L651582 had little effect on muscarinic m5 receptor-stimulated release of inositol phosphates or cAMP accumulation. Moreover, L651582 had little effect on muscarinic m2 receptor-mediated inhibition of forskolin-stimulated cAMP accumulation. Above 10 microM, L651582 inhibited all second messenger pathways tested and inhibited cell growth, suggesting its action may be less specific and toxic at these concentrations.
Felder
C C
CC
Laboratory of Cell Biology, National Institute of Mental Health, Bethesda, Maryland.
Ma
A L
AL
Liotta
L A
LA
Kohn
E C
EC
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D007295:Inositol Phosphates / Q000096:biosynthesis; D007700:Kinetics; D011976:Receptors, Muscarinic / Q000502:physiology*; D014162:Transfection; D014230:Triazoles
D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D007295:Inositol Phosphates; D011976:Receptors, Muscarinic; D014230:Triazoles; D016718:Arachidonic Acid; D000620:Aminoimidazole Carboxamide; C062058:carboxyamido-triazole; D002217:Carbachol; D000242:Cyclic AMP; D002118:Calcium