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首页> 外文期刊>Journal of Medicinal Chemistry >The alkaloid conessine and analogues as potent histamine H-3 receptor antagonists
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The alkaloid conessine and analogues as potent histamine H-3 receptor antagonists

机译：生物碱可西宁和类似物作为有效的组胺H-3受体拮抗剂

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The naturally Occurring alkaloid, conessine (6), was discovered to bind to histamine H-3 receptors in a radioligand-based high-throughput screen. Conessine displayed high affinity at both rat and human H-3 receptors (pK(i) = 7.61 and 8.27) and generally high selectivity against other sites, including histamine receptors H-1, H-2, and H-4. Conessine was found to efficiently penetrate the CNS and reach very high brain concentration,,,. Although the very slow CNS clearance and strong binding to adrenergic receptors discouraged focus on conessine itself for further development, its potency and novel steroid-based skeleton motivated further chemical investigation. Modification based on introducing diversity at the 3-nitrogen position generated a new series of H-3 antagonists with higher in vitro potency, improved target selectivity, and more favorable drug-like properties. One optimized analogue (13c) was examined in detail and was found to be efficacious in animal behavioral model of cognition.
机译：在基于放射性配体的高通量筛选中，发现天然存在的生物碱，可西碱（6）与组胺H-3受体结合。 Conessine对大鼠和人类H-3受体均显示出高亲和力（pK（i）= 7.61和8.27），并且对其他位点（包括组胺受体H-1，H-2和H-4）的选择性通常较高。发现Conessine可有效渗透CNS并达到很高的大脑浓度。尽管非常缓慢的中枢神经系统清除率和与肾上腺素受体的牢固结合不鼓励人们将注意力集中在可西宁本身上，以进一步发展，但其功效和新型基于类固醇的骨架激发了进一步的化学研究。基于在3-氮位置引入多样性的修饰，产生了一系列新的H-3拮抗剂，它们具有更高的体外效能，更高的靶标选择性和更有利的类药物特性。详细研究了一种优化的类似物（13c），发现其在动物行为认知模型中有效。

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