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首页> 外文期刊>Journal of Medicinal Chemistry >Structural Simplification of a Tetrahydroquinoline-Core Peptidomimetic mu-Opioid Receptor (MOR) Agonist/delta-Opioid Receptor (DOR) Antagonist Produces Improved Metabolic Stability
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Structural Simplification of a Tetrahydroquinoline-Core Peptidomimetic mu-Opioid Receptor (MOR) Agonist/delta-Opioid Receptor (DOR) Antagonist Produces Improved Metabolic Stability

机译：四碳喹啉核肽瘤瘤瘤 - 阿片受体（MOR）激动剂/δ-阿片受体（DOR）拮抗剂的结构简化产生改善的代谢稳定性

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We have previously reported a series of mu-opioid receptor (MOR) agonist/delta-opioid receptor (DOR) antagonist ligands to serve as potential nonaddictive opioid analgesics. These ligands have been shown to be active in vivo, do not manifest withdrawal syndromes or reward behavior in conditioned-place preference assays in mice, and do not produce dependence. Although these attributes are promising, these analogues exhibit poor metabolic stability in mouse liver microsomes, likely due to the central tetrahydroquinoline scaffold in this series. As such, a structure activity relationship (SAR) campaign was pursued to improve their metabolic stability. This resulted in a shift from our original bicyclic tetrahydroquinoline core to a monocyclic benzylic-core system. By eliminating one of the rings in this scaffold and exploring the SAR of this new core, two promising analogues were discovered. These analogues (5l and 5m) had potency and efficacy values at MOR better or comparable to morphine, retained their DOR-antagonist properties, and showed a 10-fold improvement in metabolic stability.
机译：我们以前报道了一系列Mu-阿片受体（Mor）激动剂/δ-阿片受体（DOR）拮抗剂配体，以作为潜在的非少量阿片类镇痛药。这些配体已被证明在体内活性，在小鼠中没有表现出戒断综合征或奖励行为，并且不会产生依赖性。虽然这些属性是有希望的，但这些类似物在小鼠肝脏微粒体中表现出差的代谢稳定性，可能由于该系列中的中央四氢喹啉支架。因此，追求了结构活动关系（SAR）广告系列以提高其代谢稳定性。这导致我们原始双环四喹啉核的转变为单环苄基核心系统。通过消除这种脚手架中的一个环并探索这种新核心的SAR，发现了两个有前途的类似物。这些类似物（5L和5M）具有更好或与吗啡的效力和功效值，保留了它们的DOR-拮抗剂性能，并显示了代谢稳定性的10倍。

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