McKinney M, Pfenning M, Richelson E
Biochem Pharmacol. 1986 Aug 1;35(15):2615-22. doi: 10.1016/0006-2952(86)90061-4.
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.
由于抗肿瘤药物卡醋胺会在患者中引起神经精神效应，我们研究了其对培养的神经母细胞瘤细胞（小鼠克隆N1E-115）神经化学的影响。该药物导致[3H]环鸟苷酸水平短暂升高，这种升高不受受体拮抗剂的阻断，也不受组胺或毒蕈碱受体脱敏的影响。卡醋胺反应的半数有效浓度（EC50）为635微摩尔。用卡醋胺预孵育细胞会导致毒蕈碱受体介导的[3H]环鸟苷酸形成受到抑制，半数抑制浓度（IC50）为450微摩尔。卡醋胺以非竞争性方式抑制匀浆中的基础鸟苷酸环化酶活性，抑制常数（Ki）值为162微摩尔。该药物还抑制匀浆中硝普钠刺激的鸟苷酸环化酶。卡醋胺在完整细胞或匀浆中均不抑制基础腺苷酸环化酶活性，但抑制前列腺素E1（PGE1）或福斯高林激活的腺苷酸环化酶。毒蕈碱受体介导的PGE1刺激的[3H]环腺苷酸形成的减少不受影响。在匀浆中抑制PGE1激活的腺苷酸环化酶的Ki为110微摩尔。卡醋胺是乙酰胆碱酯酶的竞争性抑制剂，Ki值为8微摩尔。该药物不抑制但轻微刺激N1E-115细胞中的单胺氧化酶活性。结果表明，卡醋胺可以以与其神经精神效应相关的方式影响培养的神经细胞中的几种神经化学系统。因此，N1E-115克隆似乎可用于评估与神经系统相互作用的药物的一些分子药理作用。
