Synthesis and Pharmacological Evaluation of 5-Pyrrolidinylquinoxalines as a Novel Class of Peripherally Restricted 魏-Opioid Receptor Agonists

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• 作者：Christian Bourgeois ; Elena Werfel ; Fabian Galla ; Kirstin Lehmkuhl ; H茅ctor Torres-G贸mez ; Dirk Schepmann ; Babette K枚gel ; Thomas Christoph ; Wolfgang Stra脽burger ; Werner Englberger ; Michael Soeberdt ; Sabine H眉wel ; Hans-Joachim Galla ; Bernhard W眉nsch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6845-6860
• 全文大小：545K
• ISSN：1520-4804

文摘

5-Pyrrolidinyl substituted perhydroquinoxalines were designed as conformationally restricted 魏-opioid receptor agonists restricted to the periphery. The additional N atom of the quinoxaline system located outside the ethylenediamine 魏 pharmacophore allows the fine-tuning of the pharmacodynamic and pharmacokinetic properties. The perhydroquinoxalines were synthesized stereoselectively using the concept of late stage diversification of the central building blocks 14. In addition to high 魏-opioid receptor affinity they demonstrate high selectivity over 渭, 未, 蟽₁, 蟽₂, and NMDA receptors. In the [³⁵S]GTP纬S assay full agonism was observed. Because of their high polarity, the secondary amines 14a (log聽D_7.4 = 0.26) and 14b (log聽D_7.4 = 0.21) did not penetrate an artificial blood鈥揵rain barrier. 14b was able to inhibit the spontaneous pain reaction after rectal mustard oil application to mice (ED₅₀ = 2.35 mg/kg). This analgesic effect is attributed to activation of peripherally located 魏 receptors, since 14b did not affect centrally mediated referred allodynia and hyperalgesia.