Candura S M, Coccini T, Manzo L, Costa L G
Department of Environmental Health, University of Washington, Seattle 98195.
J Neurochem. 1990 Nov;55(5):1741-8. doi: 10.1111/j.1471-4159.1990.tb04964.x.
Sigma-receptors are nonopioid, nondopaminergic receptors that bind with high affinity several antipsychotic drugs and appear to be involved in regulation of posture and movement. The second messenger system coupled to these receptors is still unknown. Recently, an inhibitory effect of various sigma-compounds on carbachol-stimulated phosphoinositide metabolism has been reported. We have investigated the effect of six sigma-compounds on carbachol- and norepinephrine-stimulated 3H-inositol phosphate accumulation in rat cerebral cortex slices. All compounds tested had a dose-dependent inhibitory effect on both systems, although their order of potency differed between neurotransmitters. Pentazocine and 1,3-di-o-tolylguanidine were the most potent inhibitors of carbachol-stimulated phosphoinositide turnover (IC50 = 31.5 and 45.7 microM, respectively), while haloperidol showed the greatest potency on the norepinephrine-coupled system (IC50 = 3.5 microM). In the presence of IC50 concentrations of these inhibitors, the dose-response curves for the agonists were shifted to the right and the EC50 values were significantly increased. Sigma-compounds also inhibited the binding of [3H]quinuclidinyl benzilate to muscarinic receptors and of [3H]prazosin to alpha 1-adrenoceptors in cortical membranes. In the presence of IC50 concentration (11 microM) of 1,3-di-o-tolylguanidine, no differences were found in the maximal number of muscarinic binding sites, whereas the dissociation constant increased approximately fivefold, indicating a decrease of the radioligand's affinity for the receptor. These results indicate that sigma-compounds, at micromolar concentrations, inhibit muscarinic and alpha 1-adrenergic receptor-coupled phosphoinositide metabolism, probably through an interaction with the neurotransmitter recognition sites.
西格玛受体是非阿片类、非多巴胺能受体，它能与多种抗精神病药物高亲和力结合，并且似乎参与姿势和运动的调节。与这些受体偶联的第二信使系统仍不清楚。最近，有报道称各种西格玛化合物对卡巴胆碱刺激的磷酸肌醇代谢有抑制作用。我们研究了六种西格玛化合物对大鼠大脑皮层切片中卡巴胆碱和去甲肾上腺素刺激的3H-肌醇磷酸积累的影响。所有测试的化合物对这两个系统都有剂量依赖性抑制作用，尽管它们对不同神经递质的效力顺序有所不同。喷他佐辛和1,3-二邻甲苯基胍是卡巴胆碱刺激的磷酸肌醇周转最有效的抑制剂（IC50分别为31.5和45.7微摩尔），而氟哌啶醇对去甲肾上腺素偶联系统显示出最大的效力（IC50 = 3.5微摩尔）。在这些抑制剂的IC50浓度存在下，激动剂的剂量反应曲线向右移动，EC50值显著增加。西格玛化合物还抑制了[3H]喹核醇基苯甲酸酯与皮层膜中毒蕈碱受体以及[3H]哌唑嗪与α1-肾上腺素受体的结合。在1,3-二邻甲苯基胍的IC50浓度（11微摩尔）存在下，毒蕈碱结合位点的最大数量没有差异，而解离常数增加了约五倍，表明放射性配体对受体的亲和力降低。这些结果表明，微摩尔浓度的西格玛化合物可能通过与神经递质识别位点相互作用，抑制毒蕈碱和α1-肾上腺素能受体偶联的磷酸肌醇代谢。
