TY - JOUR
T1 - Effect of the antitumor drug caracemide on the neurochemistry of murine neuroblastoma cells (clone N1E-115)
AU - Mckinney, Michael
AU - Pfenning, Michael
AU - Richelson, Elliott
N1 - Funding Information:
Acknowledgements-This work was supportedb y Public Health ServiceG rants MH 27692a nd CA 34300to Elliott Richelson, and NS21319to Michael McKinney, and by the Mayo Foundation.
PY - 1986/8/1
Y1 - 1986/8/1
N2 - 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 μM. Preincubation of cells with caracemide led to the inhibition of muscarinic receptor-mediated [3H]cyclic GMP formation with an ic50 of 450 μm. Caracemide inhibited basal guanylate cyclase activity in homogenates noncompetitively with a Ki, value of 162 μM. 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 μM. Caracemide was a competitive inhibitor of acetylcholinesterase with a K1, value of 8 μM. 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.
AB - 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 μM. Preincubation of cells with caracemide led to the inhibition of muscarinic receptor-mediated [3H]cyclic GMP formation with an ic50 of 450 μm. Caracemide inhibited basal guanylate cyclase activity in homogenates noncompetitively with a Ki, value of 162 μM. 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 μM. Caracemide was a competitive inhibitor of acetylcholinesterase with a K1, value of 8 μM. 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.
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U2 - 10.1016/0006-2952(86)90061-4
DO - 10.1016/0006-2952(86)90061-4
M3 - Article
C2 - 2874811
AN - SCOPUS:0022496374
SN - 0006-2952
VL - 35
SP - 2615
EP - 2622
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 15
ER -