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Isolation and Pharmacological Characterization of Six Opioidergic Picralima nitida Alkaloids
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-12-16 , DOI: 10.1021/acs.jnatprod.0c01036 Simone M Creed 1 , Anna M Gutridge 2 , Malaika D Argade 1 , Madeline R Hennessy 1 , J Brent Friesen 3 , Guido F Pauli 3 , Richard M van Rijn 4 , Andrew P Riley 1
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-12-16 , DOI: 10.1021/acs.jnatprod.0c01036 Simone M Creed 1 , Anna M Gutridge 2 , Malaika D Argade 1 , Madeline R Hennessy 1 , J Brent Friesen 3 , Guido F Pauli 3 , Richard M van Rijn 4 , Andrew P Riley 1
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The seeds of the akuamma tree (Picralima nitida) have been used as a traditional treatment for pain and fever. Previous studies have attributed these effects to a series of indole alkaloids found within the seed extracts; however, these pharmacological studies were significantly limited in scope. Herein, an isolation protocol employing pH-zone-refining countercurrent chromatography was developed to provide six of the akuamma alkaloids in high purity and quantities sufficient for more extensive biological evaluation. Five of these alkaloids, akuammine (1), pseudo-akuammigine (3), akuammicine (4), akuammiline (5), and picraline (6), were evaluated against a panel of >40 central nervous system receptors to identify that their primary targets are the opioid receptors. Detailed in vitro investigations revealed 4 to be a potent kappa opioid receptor agonist, and three alkaloids (1–3) were shown to have micromolar activity at the mu opioid receptor. The mu opioid receptor agonists were further evaluated for analgesic properties but demonstrated limited efficacy in assays of thermal nociception. These findings contradict previous reports of the antinociceptive properties of the P. nitida alkaloids and the traditional use of akuamma seeds as analgesics. Nevertheless, their opioid-preferring activity does suggest the akuamma alkaloids provide distinct scaffolds from which novel opioids with unique pharmacologic properties and therapeutic utility can be developed.
中文翻译：
六种阿片类苦味素生物碱的分离和药理学表征
akuamma 树（Picralima nitida）的种子已被用作治疗疼痛和发烧的传统疗法。先前的研究将这些影响归因于种子提取物中发现的一系列吲哚生物碱。然而，这些药理学研究的范围明显有限。在此，开发了一种采用 pH 区精制逆流色谱法的分离方案，以提供六种高纯度的 akuamma 生物碱，其数量足以进行更广泛的生物学评价。对这些生物碱中的五种，akuammine ( 1 )、pseudo-akuammigine ( 3 )、akuammicine ( 4 )、akuammiline ( 5 ) 和 picraline ( 6 )，针对超过 40 个中枢神经系统受体进行评估，以确定它们的主要作用目标是阿片受体。详细的体外研究表明4是一种有效的 kappa 阿片受体激动剂，三种生物碱 ( 1 – 3 ) 对 mu 阿片受体具有微摩尔活性。mu阿片受体激动剂的镇痛特性被进一步评估，但在热伤害感受测定中显示出有限的功效。这些发现与之前关于P.nitida生物碱的抗伤害特性和 akuamma 种子作为镇痛药的传统用途的报道相矛盾。然而，它们的阿片类药物偏好活性确实表明 akuamma 生物碱提供了独特的支架，可以从中开发出具有独特药理特性和治疗效用的新型阿片类药物。
更新日期：2021-01-22
中文翻译：
六种阿片类苦味素生物碱的分离和药理学表征
akuamma 树（Picralima nitida）的种子已被用作治疗疼痛和发烧的传统疗法。先前的研究将这些影响归因于种子提取物中发现的一系列吲哚生物碱。然而，这些药理学研究的范围明显有限。在此，开发了一种采用 pH 区精制逆流色谱法的分离方案，以提供六种高纯度的 akuamma 生物碱，其数量足以进行更广泛的生物学评价。对这些生物碱中的五种，akuammine ( 1 )、pseudo-akuammigine ( 3 )、akuammicine ( 4 )、akuammiline ( 5 ) 和 picraline ( 6 )，针对超过 40 个中枢神经系统受体进行评估，以确定它们的主要作用目标是阿片受体。详细的体外研究表明4是一种有效的 kappa 阿片受体激动剂，三种生物碱 ( 1 – 3 ) 对 mu 阿片受体具有微摩尔活性。mu阿片受体激动剂的镇痛特性被进一步评估，但在热伤害感受测定中显示出有限的功效。这些发现与之前关于P.nitida生物碱的抗伤害特性和 akuamma 种子作为镇痛药的传统用途的报道相矛盾。然而，它们的阿片类药物偏好活性确实表明 akuamma 生物碱提供了独特的支架，可以从中开发出具有独特药理特性和治疗效用的新型阿片类药物。
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