Effect of the antitumor drug caracemide on the neurochemistry of murine neuroblastoma cells (clone N1E-115).
Because the antitumor drug caracemide causes neuropsychiatric effects in patients, we investigated its effects on the neurochemistry of cultured neuroblastoma cells (murine clone N1E-115). The drug caused a transient elevation in the level of [3H]cyclic GMP that was not blocked by receptor antagonists or by desensitization of histamine or muscarinic receptors. The EC50 for the response to caracemide was 635 microM. Preincubation of cells with caracemide led to the inhibition of muscarinic receptor-mediated [3H]cyclic GMP formation with an IC50 of 450 microM. Caracemide inhibited basal guanylate cyclase activity in homogenates noncompetitively with a Ki value of 162 microM. The drug also inhibited sodium nitroprusside-stimulated guanylate cyclase in homogenates. Caracemide did not inhibit basal adenylate cyclase activity in either intact cells or homogenates, but inhibited adenylate cyclase activated by prostaglandin E1 (PGE1) or forskolin. The muscarinic receptor-mediated reduction of PGE1-stimulated [3H]cyclic AMP formation was not affected. The Ki for the inhibition of PGE1-activated adenylate cyclase in homogenates was 110 microM. Caracemide was a competitive inhibitor of acetylcholinesterase with a Ki value of 8 microM. The drug did not inhibit, but slightly stimulated, monoamine oxidase activity in N1E-115 cells. The results indicate that caracemide can affect several neurochemical systems in neural cells in culture in a way that correlates with its neuropsychiatric effects. The N1E-115 clone thus appears to be useful for evaluating some of the molecular pharmacological effects of drugs interacting with the nervous system.
D000067956:Adenylyl Cyclase Inhibitors; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D009637:Masoprocol; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009420:Nervous System / Q000187:drug effects*; D009447:Neuroblastoma / Q000201:enzymology*; D011976:Receptors, Muscarinic / Q000187:drug effects
D000067956:Adenylyl Cyclase Inhibitors; D000970:Antineoplastic Agents; D002396:Catechols; D002800:Cholinesterase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D011976:Receptors, Muscarinic; D009637:Masoprocol; D006162:Guanylate Cyclase; D000527:Alprostadil; D006152:Cyclic GMP; C044466:caracemide; D004229:Dithiothreitol; D006918:Hydroxyurea