Micale Nicola, Colleoni Simona, Postorino Giovanna, Pellicanò Alessia, Zappalà Maria, Lazzaro John, Diana Valentina, Cagnotto Alfredo, Mennini Tiziana, Grasso Silvana
Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Messina, Italy.
Bioorg Med Chem. 2008 Mar 1;16(5):2200-11. doi: 10.1016/j.bmc.2007.11.080. Epub 2007 Dec 5.
In the search for AMPA receptor (AMPAR) antagonists, 2,3-benzodiazepines represent a family of specific noncompetitive antagonists with anticonvulsant and neuroprotective properties. We have previously shown that 2,3-benzodiazepin-4-ones possess marked anticonvulsant properties and high affinity for the noncompetitive binding site of the AMPAR complex. In this paper, we report the synthesis and pharmacological characterization of a full set of 2,3-benzodiazepin-4-ones in order to better define the structure-activity relationship (SAR) of this class of compounds. Binding assays and functional tests were performed to evaluate the antagonistic activity at the AMPARs. Through these results we have identified a potent AMPAR antagonist, 1-(4-amino-3-methylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one (5c). This compound noncompetitively inhibited AMPAR-mediated toxicity in primary mouse hippocampal cultures with an IC(50) of 1.6muM and blocked kainate-induced calcium influx in rat cerebellar granule cells with an IC(50) of 6.4muM. Thus, 5c has the in vitro potential as therapeutic drug in the treatment of various neurological disorders.
在寻找α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）拮抗剂的过程中，2,3-苯并二氮杂卓代表了一类具有抗惊厥和神经保护特性的特异性非竞争性拮抗剂。我们之前已经表明，2,3-苯并二氮杂卓-4-酮具有显著的抗惊厥特性，并且对AMPAR复合物的非竞争性结合位点具有高亲和力。在本文中，我们报告了一整套2,3-苯并二氮杂卓-4-酮的合成及药理学特性，以便更好地确定这类化合物的构效关系（SAR）。进行了结合试验和功能测试，以评估对AMPARs的拮抗活性。通过这些结果，我们鉴定出一种强效的AMPAR拮抗剂，1-(4-氨基-3-甲基苯基)-3,5-二氢-7,8-亚乙基二氧基-4H-2,3-苯并二氮杂卓-4-酮（5c）。该化合物在原代小鼠海马培养物中以1.6μM的IC(50)非竞争性抑制AMPAR介导的毒性，并在大鼠小脑颗粒细胞中以6.4μM的IC(50)阻断红藻氨酸诱导的钙内流。因此，5c在体外具有作为治疗各种神经疾病的治疗药物的潜力。
