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Structure activity relationship exploration of 5-hydroxy-2-(3-phenylpropyl)chromones as a unique 5-HT2B receptor antagonist scaffold.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-08-24 , DOI: 10.1016/j.bmcl.2020.127511
Minsoo Kim 1 , Myles Truss 1 , Piyusha P Pagare 2 , Martha A Essandoh 3 , Yan Zhang 2 , Dwight A Williams 1
Affiliation  

Antagonists for the serotonin receptor 2B (5-HT2B) have clinical applications towards migraine, anxiety, irritable bowl syndrome, and MDMA abuse; however, few selective 5-HT2B antagonists have been identified. Previous studies from these labs identified a natural product, 5-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 2) as the first non-nitrogenous ligand for the 5-HT2B receptor. Studies on 5-HPEC optimization led to the identification of 5-hydroxy-2-(3-phenylpropyl)chromone (5-HPPC, 3), which showed a tenfold improvement in binding affinity over 2 at 5-HT2B. This study aimed to further improve receptor pharmacology of this unique scaffold. Guided by molecular modeling studies modifications at the C-3′ and C-4′ positions of 3 were made to probe their effects on ligand binding affinity and efficacy. Among the derivatives synthesized 5-hydroxy-2-(3-(3-cyanophenyl)propyl)chromone (5-HCPC, 3d) showed the most promise with a multifold improvement in binding affinity (pKi = 7.1 ± 0.07) over 3 with retained antagonism.



中文翻译:

作为一个独特的5-HT2B受体拮抗剂支架的5-羟基-2-(3-苯基丙基)色酮的结构活性关系探索。

血清素2B(5-HT 2B)拮抗剂在偏头痛,焦虑症,易怒性碗综合征和MDMA滥用方面具有临床应用;然而,几乎没有发现选择性的5-HT 2B拮抗剂。这些实验室的先前研究确定了天然产物5-羟基-2-(2-苯乙基)色酮(5-HPEC,2)作为5-HT 2B受体的第一个非氮配体。对5-HPEC优化的研究导致鉴定了5-羟基-2-(3-苯基丙基)色酮(5-HPPC,3),在5-HT 2B上结合亲和力比2提高了十倍。这项研究旨在进一步改善这种独特支架的受体药理学。通过分子建模研究修改在C-3'和C-4'的位置的引导3作了探讨其对配体结合亲和力和效力的影响。在合成的衍生物中,5-羟基-2-(3-(3-氰基苯基)丙基)发色酮(5-HCPC,3d)表现出最有希望的结合亲和力(pK i  = 7.1±0.07)的提高超过3倍。保留对抗性。

更新日期:2020-08-29
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