Parallel Synthesis of Hexahydrodiimidazodiazepines Heterocyclic Peptidomimetics and Their in Vitro and in Vivo Activities at μ (MOR), δ (DOR), and κ (KOR) Opioid Receptors
Parallel Synthesis of Hexahydrodiimidazodiazepines Heterocyclic Peptidomimetics and Their in Vitro and in Vivo Activities at μ (MOR), δ (DOR), and κ (KOR) Opioid Receptors
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DOI：
10.1021/jm501637c
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发表时间：
2015-06-25
影响因子：
7.3
通讯作者：
Nefzi, Adel
中科院分区：
文献类型：
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作者：
Eans, Shainnel O.;Ganno, Michelle L.;Nefzi, Adel
在镇痛药的开发中具有混合阿片激动剂活性，外周选择性活性预计可减少副作用，最大限度地减少呼吸抑制并增强产生显着更安全的镇痛治疗剂的特性。我们从还原的三肽合成了二氮杂环化合物。用放射性配体竞争结合测定进行的体外筛选证明了对所有系列的μ（莫尔）、δ（DOR）和κ（KOR）阿片受体的可变亲和力，其中二咪唑二氮杂卓14（2065-14）对DOR和KOR显示出良好的亲和力。14的中枢（冰冷）、腹膜内（ip）或口服（po）给药在小鼠中产生剂量依赖性的阿片样受体介导的抗伤害感受，如从55 ℃温水尾部戒断测定所确定的。直到90分钟后，在脑中仅发现痕量的化合物14，表明BBB渗透性差和可能的外周受限活性。中央管理的14没有产生运动的影响，急性抗伤害性耐受，或条件性位置偏好或厌恶。这些数据表明，这些二氮杂环混合活性阿片受体激动剂可能具有作为新的镇痛药的潜力，使用的责任较少。
In the development of analgesics With mixed-opioid agonist activity, peripherally selective activity is expected to decrease side effects, minimizing respiratory depression and reinforcing properties generating significantly safer analgesic therapeutics. We synthesized diazaheterocyclics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for mu (MOR), delta (DOR), and kappa (KOR) opioid receptors across the series, with the diimidazodiazepine 14 (2065-14) displaying good affinity for DOR and KOR. Central (icy), intraperitoneal (ip), or oral (po) administration of 14 produced dose-dependent, opioid-receptor mediated antinociception in the mouse, as determined from a 55 degrees C warm-water tail-withdrawal assay. Only trace amounts of compound 14 was found in brain up to 90 min later, suggesting poor BBB penetration and possible peripherally restricted activity. Central administration of 14 did not produce locomotor effects, acute antinociceptive tolerance, or conditioned-place preference or aversion. The data suggest these diazaheterocyclic mixed activity opioid receptor agonists may hold potential as new analgesics with fewer liabilities of use.