Felder C C, Ma A L, Liotta L A, Kohn E C
Laboratory of Cell Biology, National Institute of Mental Health, Bethesda, Maryland.
J Pharmacol Exp Ther. 1991 Jun;257(3):967-71.
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.
L651582是一种羧酰胺基氨基咪唑，先前已证明它在低微摩尔浓度下具有抗增殖和抗转移特性；然而，对其细胞作用机制知之甚少。对L651582阻断受体刺激的钙内流、花生四烯酸释放、肌醇磷酸和环磷酸腺苷（cAMP）生成的能力进行了测试。这些信号转导途径由转染并在中国仓鼠卵巢细胞中表达的毒蕈碱受体激活。L651582在低微摩尔浓度下阻断了毒蕈碱m5受体刺激的45Ca++内流和花生四烯酸的释放。先前已表明，毒蕈碱受体刺激的花生四烯酸释放依赖于钙内流而非细胞内钙释放，这表明L651582可能作为钙通道阻滞剂有用。在低微摩尔浓度下，L651582对毒蕈碱m5受体刺激的肌醇磷酸释放或cAMP积累几乎没有影响。此外，L651582对毒蕈碱m2受体介导的对福斯高林刺激的cAMP积累的抑制作用几乎没有影响。在10 microM以上，L651582抑制了所有测试的第二信使途径并抑制了细胞生长，表明其在这些浓度下的作用可能特异性较低且具有毒性。
