Benzimidazolone-based selective σ2 receptor ligands: Synthesis and pharmacological evaluation
Benzimidazolone-based selective σ2 receptor ligands: Synthesis and pharmacological evaluation
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DOI：
10.1016/j.ejmech.2019.01.019
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发表时间：
2019-03-01
影响因子：
6.7
通讯作者：
McCurdy, Christopher R.
中科院分区：
文献类型：
--
作者：
Intagliata, Sebastiano;Alsharif, Walid F.;McCurdy, Christopher R.
σ受体（σ Rs）被认为是开发新药物以解决几种疾病的重要和有效的靶标。它们在许多中枢神经系统疾病、神经性疼痛、成瘾和癌症中的潜在参与已被广泛报道。特别地，σ R-2已被鉴定为用于开发旨在治疗与滥用药物相关的负面作用的药剂的潜在靶标。作为我们先前努力开发新的选择性σ R-2配体的延续，设计、合成和表征了一系列苯并咪唑酮衍生物。通过体外放射性配体结合试验评估新合成的配体，以确定它们对sigma（1）和sigma（2）受体的亲和力和选择性。几种衍生物显示出对sigma R-2的高亲和力（Ki = 0.66-68.5 nM），并且与sigma R-1（sigma（1）/sigma（2）= 5.8-1139）相比，从优选到选择性变化。其中，化合物1-{4-[4-（4-氟苯基）哌嗪-1-基]丁基}-3-丙基-1，3-二氢苯并咪唑-2-酮二盐酸盐（14）在啮齿动物模型中注射10 mg/kg（i. p.）后显示出产生可卡因惊厥作用的剂量依赖性降低的能力。这些初步结果支持使用选择性σ R-2配体开发有用的药理学工具或潜在的药物治疗可卡因毒性。(C)2019 Elsevier Masson SAS。All rights reserved.
Sigma receptors (sigma Rs) are considered to be a significant and valid target for developing new medications to address several diseases. Their potential involvement in numerous central nervous system disorders, neuropathic pain, addiction, and cancer has been extensively reported. In particular, the sigma R-2 has been identified as potential target for the development of pharmaceutical agents intended to treat the negative effects associated with drugs of abuse. As a continuation of our previous efforts to develop new selective sigma R-2 ligands, a series of benzimidazolone derivatives were designed, synthesized, and characterized. The newly synthesized ligands were evaluated through in vitro radioligand binding assays to determine their affinity and selectivity towards both sigma(1) and sigma(2) receptors. Several derivatives displayed high affinity for the sigma R-2 (K-i = 0.66-68.5 nM) and varied from preferring to selective, compared to sigma R-1 (sigma(1)/sigma(2) = 5.8-1139). Among them, compound 1-{4-[4-(4-fluorophenyl)piperazin-1-yl]butyl}-3-propyl-1,3-dihydrobenzimidazol-2-one dihydrochloride (14) displayed the ability to produce a dose-dependent reduction in the convulsive effects of cocaine in a rodent model after injecting 10 mg/kg (i.p.). These preliminary results support the use of selective sigma R-2 ligands in the development of useful pharmacological tools or potential pharmacotherapies for cocaine toxicity. (C) 2019 Elsevier Masson SAS. All rights reserved.